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Sample records for inhibits hepatocellular carcinoma

  1. Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models.

    Science.gov (United States)

    French, Dorothy M; Lin, Benjamin C; Wang, Manping; Adams, Camellia; Shek, Theresa; Hötzel, Kathy; Bolon, Brad; Ferrando, Ronald; Blackmore, Craig; Schroeder, Kurt; Rodriguez, Luis A; Hristopoulos, Maria; Venook, Rayna; Ashkenazi, Avi; Desnoyers, Luc R

    2012-01-01

    The fibroblast growth factor (FGF)-FGF receptor (FGFR) signaling system plays critical roles in a variety of normal developmental and physiological processes. It is also well documented that dysregulation of FGF-FGFR signaling may have important roles in tumor development and progression. The FGFR4-FGF19 signaling axis has been implicated in the development of hepatocellular carcinomas (HCCs) in mice, and potentially in humans. In this study, we demonstrate that FGFR4 is required for hepatocarcinogenesis; the progeny of FGF19 transgenic mice, which have previously been shown to develop HCCs, bred with FGFR4 knockout mice fail to develop liver tumors. To further test the importance of FGFR4 in HCC, we developed a blocking anti-FGFR4 monoclonal antibody (LD1). LD1 inhibited: 1) FGF1 and FGF19 binding to FGFR4, 2) FGFR4-mediated signaling, colony formation, and proliferation in vitro, and 3) tumor growth in a preclinical model of liver cancer in vivo. Finally, we show that FGFR4 expression is elevated in several types of cancer, including liver cancer, as compared to normal tissues. These findings suggest a modulatory role for FGFR4 in the development and progression of hepatocellular carcinoma and that FGFR4 may be an important and novel therapeutic target in treating this disease.

  2. Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models.

    Directory of Open Access Journals (Sweden)

    Dorothy M French

    Full Text Available The fibroblast growth factor (FGF-FGF receptor (FGFR signaling system plays critical roles in a variety of normal developmental and physiological processes. It is also well documented that dysregulation of FGF-FGFR signaling may have important roles in tumor development and progression. The FGFR4-FGF19 signaling axis has been implicated in the development of hepatocellular carcinomas (HCCs in mice, and potentially in humans. In this study, we demonstrate that FGFR4 is required for hepatocarcinogenesis; the progeny of FGF19 transgenic mice, which have previously been shown to develop HCCs, bred with FGFR4 knockout mice fail to develop liver tumors. To further test the importance of FGFR4 in HCC, we developed a blocking anti-FGFR4 monoclonal antibody (LD1. LD1 inhibited: 1 FGF1 and FGF19 binding to FGFR4, 2 FGFR4-mediated signaling, colony formation, and proliferation in vitro, and 3 tumor growth in a preclinical model of liver cancer in vivo. Finally, we show that FGFR4 expression is elevated in several types of cancer, including liver cancer, as compared to normal tissues. These findings suggest a modulatory role for FGFR4 in the development and progression of hepatocellular carcinoma and that FGFR4 may be an important and novel therapeutic target in treating this disease.

  3. Mammalian target of rapamycin inhibition in hepatocellular carcinoma

    Science.gov (United States)

    Ashworth, René E; Wu, Jennifer

    2014-01-01

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is the only available systemic agent for treatment of HCC that improves overall survival for patients with advanced stage disease; unfortunately, an effective second-line agent for the treatment of progressive or sorafenib-resistant HCC has yet to be identified. This review focuses on components of the mammalian target of rapamycin (mTOR) pathway, its role in HCC pathogenesis, and dual mTOR inhibition as a therapeutic option with potential efficacy in advanced HCC. There are several important upstream and downstream signals in the mTOR pathway, and alternative tumor-promoting pathways are known to exist beyond mTORC1 inhibition in HCC. This review analyzes the relationships of the upstream and downstream regulators of mTORC1 and mTORC2 signaling; it also provides a comprehensive global picture of the interaction between mTORC1 and mTORC2 which demonstrates the pre-clinical relevance of the mTOR pathway in HCC pathogenesis and progression. Finally, it provides scientific rationale for dual mTORC1 and mTORC2 inhibition in the treatment of HCC. Clinical trials utilizing mTORC1 inhibitors and dual mTOR inhibitors in HCC are discussed as well. The mTOR pathway is comprised of two main components, mTORC1 and mTORC2; each has a unique role in the pathogenesis and progression of HCC. In phase III studies, mTORC1 inhibitors demonstrate anti-tumor activity in advanced HCC, but dual mTOR (mTORC1 and mTORC2) inhibition has greater therapeutic potential in HCC treatment which warrants further clinical investigation. PMID:25429315

  4. Xanthohumol Inhibits Notch Signaling and Induces Apoptosis in Hepatocellular Carcinoma

    OpenAIRE

    Selvi Kunnimalaiyaan; Sokolowski, Kevin M.; Mariappan Balamurugan; T. Clark Gamblin; Muthusamy Kunnimalaiyaan

    2015-01-01

    Despite improvement in therapeutic strategies, median survival in advanced hepatocellular carcinoma (HCC) remains less than one year. Therefore, molecularly targeted compounds with less toxic profiles are needed. Xanthohumol (XN), a prenylated chalcone has been shown to have anti-proliferative effects in various cancers types in vitro. XN treatment in healthy mice and humans yielded favorable pharmacokinetics and bioavailability. Therefore, we determined to study the effects of XN and underst...

  5. Mammalian target of rapamycin inhibition in hepatocellular carcinoma

    OpenAIRE

    Ashworth, René E; Wu, Jennifer

    2014-01-01

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is the only available systemic agent for treatment of HCC that improves overall survival for patients with advanced stage disease; unfortunately, an effective second-line agent for the treatment of progressive or sorafenib-resistant HCC has yet to be identified. This review focuses...

  6. Targeting FGFR4 Inhibits Hepatocellular Carcinoma in Preclinical Mouse Models

    OpenAIRE

    French, Dorothy M.; Benjamin C Lin; Manping Wang; Camellia Adams; Theresa Shek; Kathy Hötzel; Brad Bolon; Ronald Ferrando; Craig Blackmore; Kurt Schroeder; Rodriguez, Luis A.; Maria Hristopoulos; Rayna Venook; Avi Ashkenazi; Desnoyers, Luc R.

    2012-01-01

    The fibroblast growth factor (FGF)-FGF receptor (FGFR) signaling system plays critical roles in a variety of normal developmental and physiological processes. It is also well documented that dysregulation of FGF-FGFR signaling may have important roles in tumor development and progression. The FGFR4-FGF19 signaling axis has been implicated in the development of hepatocellular carcinomas (HCCs) in mice, and potentially in humans. In this study, we demonstrate that FGFR4 is required for hepatoca...

  7. Xanthohumol inhibits Notch signaling and induces apoptosis in hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Selvi Kunnimalaiyaan

    Full Text Available Despite improvement in therapeutic strategies, median survival in advanced hepatocellular carcinoma (HCC remains less than one year. Therefore, molecularly targeted compounds with less toxic profiles are needed. Xanthohumol (XN, a prenylated chalcone has been shown to have anti-proliferative effects in various cancers types in vitro. XN treatment in healthy mice and humans yielded favorable pharmacokinetics and bioavailability. Therefore, we determined to study the effects of XN and understand the mechanism of its action in HCC. The effects of XN on a panel of HCC cell lines were assessed for cell viability, colony forming ability, and cellular proliferation. Cell lysates were analyzed for pro-apoptotic (c-PARP and cleaved caspase-3 and anti-apoptotic markers (survivin, cyclin D1, and Mcl-1. XN concentrations of 5 μM and above significantly reduced the cell viability, colony forming ability and also confluency of all four HCC cell lines studied. Furthermore, growth suppression due to apoptosis was evidenced by increased expression of pro-apoptotic and reduced expression of anti-apoptotic proteins. Importantly, XN treatment inhibited the Notch signaling pathway as evidenced by the decrease in the expression of Notch1 and HES-1 proteins. Ectopic expression of Notch1 in HCC cells reverses the anti-proliferative effect of XN as evidenced by reduced growth suppression compared to control. Taken together these results suggested that XN mediated growth suppression is appeared to be mediated by the inhibition of the Notch signaling pathway. Therefore, our findings warrants further studies on XN as a potential agent for the treatment for HCC.

  8. Xanthohumol inhibits Notch signaling and induces apoptosis in hepatocellular carcinoma.

    Science.gov (United States)

    Kunnimalaiyaan, Selvi; Sokolowski, Kevin M; Balamurugan, Mariappan; Gamblin, T Clark; Kunnimalaiyaan, Muthusamy

    2015-01-01

    Despite improvement in therapeutic strategies, median survival in advanced hepatocellular carcinoma (HCC) remains less than one year. Therefore, molecularly targeted compounds with less toxic profiles are needed. Xanthohumol (XN), a prenylated chalcone has been shown to have anti-proliferative effects in various cancers types in vitro. XN treatment in healthy mice and humans yielded favorable pharmacokinetics and bioavailability. Therefore, we determined to study the effects of XN and understand the mechanism of its action in HCC. The effects of XN on a panel of HCC cell lines were assessed for cell viability, colony forming ability, and cellular proliferation. Cell lysates were analyzed for pro-apoptotic (c-PARP and cleaved caspase-3) and anti-apoptotic markers (survivin, cyclin D1, and Mcl-1). XN concentrations of 5 μM and above significantly reduced the cell viability, colony forming ability and also confluency of all four HCC cell lines studied. Furthermore, growth suppression due to apoptosis was evidenced by increased expression of pro-apoptotic and reduced expression of anti-apoptotic proteins. Importantly, XN treatment inhibited the Notch signaling pathway as evidenced by the decrease in the expression of Notch1 and HES-1 proteins. Ectopic expression of Notch1 in HCC cells reverses the anti-proliferative effect of XN as evidenced by reduced growth suppression compared to control. Taken together these results suggested that XN mediated growth suppression is appeared to be mediated by the inhibition of the Notch signaling pathway. Therefore, our findings warrants further studies on XN as a potential agent for the treatment for HCC.

  9. Inhibition of Regulatory Volume Decrease Enhances the Cytocidal Effect of Hypotonic Shock in Hepatocellular Carcinoma.

    Science.gov (United States)

    Kudou, Michihiro; Shiozaki, Atsushi; Kosuga, Toshiyuki; Ichikawa, Daisuke; Konishi, Hirotaka; Morimura, Ryo; Komatsu, Shuhei; Ikoma, Hisashi; Fujiwara, Hitoshi; Okamoto, Kazuma; Hosogi, Shigekuni; Nakahari, Takashi; Marunaka, Yoshinori; Otsuji, Eigo

    2016-01-01

    Background : Hypotonic shock induces cytocidal effects through cell rupture, and cancer therapy based on this mechanism has been clinically administered to hepatocellular carcinoma patients. We herein investigated the effectiveness of hypotonic shock combined with the inhibition of regulatory volume decrease as cancer therapy for hepatocellular carcinoma. Methods : Morphological changes in human hepatocellular carcinoma cell lines were observed under a differential interference contrast microscope connected to a high-speed digital video camera. Cell volume changes under hypotonic shock with or without chloride, potassium, or water channel blockers were observed using a high-resolution flow cytometer. In order to investigate cytocidal effects, the number of surviving cells was compared after exposure to hypotonic solution with and without each channel blocker (re-incubation experiment). Results : Video recordings showed that cells exposed to distilled water rapidly swelled and then ruptured. Cell volume measurements revealed regulatory volume decrease under mild hypotonic shock, whereas severe hypotonic shock increased the number of broken fragments as a result of cell rupture. Moreover, regulatory volume decrease was inhibited in cells treated with each channel blocker. Re-incubation experiments showed the cytocidal effects of hypotonic shock in cells exposed to hypotonic solution, and additional treatments with each channel blocker enhanced these effects. Conclusion : The inhibition of regulatory volume decrease with chloride, potassium, or water channel blockers may enhance the cytocidal effects of hypotonic shock in hepatocellular carcinoma. Hypotonic shock combined with the inhibition of regulatory volume decrease was a more effective therapy than hypotonic shock alone.

  10. WJH 6th Anniversary Special Issues(2): Hepatocellular carcinoma Mammalian target of rapamycin inhibition in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    René; E; Ashworth; Jennifer; Wu

    2014-01-01

    Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is the only available systemic agent for treatment of HCC that improves overall survival for patients with advanced stage disease; unfortunately, an effective second-line agent for the treatment of progressive or sorafenib-resistant HCC has yet to be identified. This review focuses on components of the mammalian target of rapamycin(mTOR) pathway, its role in HCC pathogenesis, and dual mTOR inhibition as a therapeutic option with potential efficacy in advanced HCC. There are several important upstream and downstream signals in the mTOR pathway, and alternative tumor-promoting pathways are known to exist beyond mTORC1 inhibition in HCC. This review analyzes the relationships of the upstream and downstream regulators of mTORC1 and mTORC2 signaling; it also provides a comprehensive global picture of the interaction between mTORC1 and mTORC2 which demonstrates the pre-clinical relevance of the mTOR pathway in HCC pathogenesis and progression. Finally, it provides scientific rationale for dual mTORC1 and mTORC2 inhibition in the treatment of HCC. Clinical trials utilizing mTORC1 inhibitors and dual mTOR inhibitors in HCC are discussed as well. The mTOR pathway is comprised of two main components, mTORC1 and mTORC2; each has a unique role in the pathogenesis and progression of HCC. In phase Ⅲ studies, mTORC1 inhibitors demonstrate anti-tumor ac-tivity in advanced HCC, but dual mTOR(mTORC1 and mTORC2) inhibition has greater therapeutic potential in HCC treatment which warrants further clinical investigation.

  11. Noscapine inhibits human hepatocellular carcinoma growth through inducing apoptosis in vitro and in vivo.

    Science.gov (United States)

    Xu, G; Niu, Z; Dong, J; Zhao, Y; Zhang, Y; Li, X

    2016-01-01

    Noscapine, a phthalideisoquinoline alkaloid derived from opium, has been demonstrated as a promising anti-tumor compound against various cancers. However, the anti-cancer activity of noscapine in hepatocellular carcinoma has not been defined. In this study, we investigate the inhibitive effects of noscapine on human hepatocellular carcinoma (HCC) using both in vitro and in vivo models. In vitro proliferation assay showed that noscapine suppressed HepG2 and Huh7 cells in dose- and time-dependent manners. With a mouse xenograft model, noscapine showed notable inhibition on HCC tumor growth in vivo without suppression of body weight. Moreover, apoptotic induction and regulation of related signalings by noscapine were examined by nuclear DNA staining, TUNEL, and western blotting assays. Results showed that noscapine induced apoptosis in HCC cells both in vitro and in vivo. Further studies indicated that noscapine induced antive-capsase-3, cleavage PARP, and decreased the ratio of Bcl-2/Bax. Hence, these data indicates that noscapine selectively suppresses HCC cell growth through apoptosis induction, providing evidence for application of noscapine as a novel agent against human hepatocellular carcinoma.

  12. Liver cancer - hepatocellular carcinoma

    Science.gov (United States)

    Primary liver cell carcinoma; Tumor - liver; Cancer - liver; Hepatoma ... Hepatocellular carcinoma accounts for most liver cancers. This type of cancer occurs more often in men than women. It is usually diagnosed in people age 50 or ...

  13. Apigenin inhibits NF-κB and snail signaling, EMT and metastasis in human hepatocellular carcinoma.

    Science.gov (United States)

    Qin, Yuan; Zhao, Dong; Zhou, Hong-Gang; Wang, Xing-Hui; Zhong, Wei-Long; Chen, Shuang; Gu, Wen-Guang; Wang, Wei; Zhang, Chun-Hong; Liu, Yan-Rong; Liu, Hui-Juan; Zhang, Qiang; Guo, Yuan-Qiang; Sun, Tao; Yang, Cheng

    2016-07-05

    Apigenin is a naturally occurring compound with anti-inflammatory, antioxidant, and anticancer properties. In this study, we investigated the effects of apigenin on migration and metastasis in experimental human hepatocellular carcinoma (HCC) cell lines in vitro and in vivo. Apigenin dose-dependently inhibited proliferation, migration, and invasion by PLC and Bel-7402 human HCC cells. It also suppressed tumor growth in PLC cell xenografts without altering body weight, thereby prolonging survival. Apigenin reduced Snai1 and NF-κB expression, reversed increases in epithelial-mesenchymal transition (EMT) marker levels, increased cellular adhesion, regulated actin polymerization and cell migration, and inhibited invasion and migration by HCC cells. Apigenin may therefore inhibit EMT by inhibiting the NF-κB/Snail pathway in human HCC.

  14. DAX-1 Inhibits Hepatocellular Carcinoma Proliferation by Inhibiting β-Catenin Transcriptional Activity

    Directory of Open Access Journals (Sweden)

    Hong-Lei Jiang

    2014-08-01

    Full Text Available Background/Aims: Hepatocellular carcinoma (HCC represents the most common type of liver cancer. DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1, an atypical member of the nuclear receptor family due to lack of classical DNA-binding domains, has been known for its fundamental roles in the development, especially in the sex determination and steroidogenesis. Previous studies also showed that DAX-1 played a critical role in endocrine and sex steroid-dependent neoplasms such as adrenocortical, pituitary, endometrial, and ovarian tumors. However, its biological roles in the development of HCC remain largely unexplored. Methods: Real-time PCR and Western blot were used to detect the expression of DAX-1 in HCC tissues and cell lines. Immunoprecipitation (IP assay was used to show the interaction between DAX-1 and β-Catenin. Small interfering RNA (siRNA was used to silence the expression of DAX-1. BrdU incorporation and Cell-cycle assays were used to detect the role of DAX-1 in HCC cells proliferation. Migration and invasion assays were carried out to test the metastasis ability of DAX-1 in HCC cells. Results: In the present study, we found that mRNA and protein levels of DAX-1 were down-regulated in HCC tissues and cell lines. Furthermore, overexpression of DAX-1 could inhibit while its knockdown using small interfering RNA promoted cell proliferation in several HCC cell lines. At the molecular level, we demonstrated that DAX-1 could interact with β-Catenin and attenuate its transcriptional activity. Conclusion: Therefore, our results suggest a previously unknown DAX-1/β-Catenin molecular network controlling HCC development.

  15. Docetaxel inhibits SMMC-7721 human hepatocellular carcinoma cells growth and induces apoptosis

    Institute of Scientific and Technical Information of China (English)

    Chang-Xin Geng; Zhao-Chong Zeng; Ji-Yao Wang

    2003-01-01

    AIM: To investigate the in vitro anti-hepatocellular carcinoma (HCC) activity of docetaxel against SMMC-7721 HCC cells and its possible mechanism.METHODS: The HCC cells were given different concentrations of docetaxel and their growth was measured by colony forming assay. Cell cycle and apoptosis were analyzed by flow cytometry and fluorescence microscopy (acridine orange/ethidium bromide double staining, AO/EB), as well as electronic microscopy. The SMMC-7721 HCC cell reactive oxygen species (ROS) and glutathione (GSH) were measured after given docetaxel.RESULTS: Docetaxel inhibited the hepatocellular carcinoma cells growth in a concentration dependent manner with IC505×10-10 M. Marked cell apoptosis and G2/M phase arrest were observed after treatment with docetaxel ≥10-8M.Docetaxel promoted SMMC-7721 HCC cells ROS generation and GSH deletion.CONCLUSION: Docetaxel suppressed the growth of SMMC7721 HCC cells in vitro by causing apoptosis and G2/M phase arrest of the human hepatoma cells, and ROS and GSH may play a key role in the inhibition of growth and induction of apoptosis.

  16. Glutathione treatment of hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Dalhoff, K; Ranek, L; Mantoni, M

    1992-01-01

    This prospective study was undertaken to substantiate observations that glutathione (GSH) inhibits or reverses tumor growth in humans with hepatocellular carcinoma (HCC), a neoplasm with an extremely poor prognosis. Eight patients with biopsy-proven HCC not amenable to surgery were given 5 g of G...

  17. Nanoparticle-formulated siRNA targeting integrins inhibits hepatocellular carcinoma progression in mice

    Science.gov (United States)

    Bogorad, Roman L; Yin, Hao; Zeigerer, Anja; Nonaka, Hidenori; Ruda, Vera; Zerial, Marino; Anderson, Daniel G; Koteliansky, Victor

    2014-01-01

    Integrins play an important role during development, regulating cell differentiation, proliferation and survival. Here we show that knockdown of integrin subunits slows down the progression of hepatocellular carcinoma (HCC). Using nanoparticulate delivery of short interfering RNAs targeting β1 and αv integrin subunits we downregulate all integrin receptors in hepatocytes. Short-term integrin knockdown (two weeks) does not cause apparent structural or functional perturbations of normal liver tissue. Alterations in liver morphology accumulate upon sustained integrin downregulation (seven weeks). The integrin knockdown leads to significant retardation of HCC progression, reducing proliferation and increasing tumour cell death. This tumour retardation is accompanied by reduced activation of MET oncogene as well as expression of its mature form on the cell surface. Our data suggest that transformed proliferating cells from HCC are more sensitive to knockdown of integrins than normal quiescent hepatocytes, highlighting the potential of siRNA-mediated inhibition of integrins as an anti-cancer therapeutic approach. PMID:24844798

  18. Pekinenin E Inhibits the Growth of Hepatocellular Carcinoma by Promoting Endoplasmic Reticulum Stress Mediated Cell Death

    Directory of Open Access Journals (Sweden)

    Lu Fan

    2017-06-01

    Full Text Available Hepatocellular carcinoma (HCC is a malignant primary liver cancer with poor prognosis. In the present study, we report that pekinenin E (PE, a casbane diterpenoid derived from the roots of Euphorbia pekinensis, has a strong antitumor activity against human HCC cells both in vitro and in vivo. PE suppressed the growth of human HCC cells Hep G2 and SMMC-7721. In addition, PE-mediated endoplasmic reticulum (ER stress caused increasing expressions of C/EBP homologous protein (CHOP, leading to apoptosis in HCC cells both in vitro and in vivo. Inhibition of ER stress with CHOP small interfering RNA or 4-phenyl-butyric acid partially reversed PE-induced cell death. Furthermore, PE induced S cell cycle arrest, which could also be partially reversed by CHOP knockdown. In all, these findings suggest that PE causes ER stress-associated cell death and cell cycle arrest, and it may serve as a potent agent for curing human HCC.

  19. LDH inhibition impacts on heat shock response and induces senescence of hepatocellular carcinoma cells.

    Science.gov (United States)

    Manerba, Marcella; Di Ianni, Lorenza; Govoni, Marzia; Roberti, Marinella; Recanatini, Maurizio; Di Stefano, Giuseppina

    2017-07-15

    In normal cells, heat shock response (HSR) is rapidly induced in response to a variety of harmful conditions and represents one of the most efficient defense mechanism. In cancer tissues, constitutive activation converts HSR into a life-threatening process, which plays a major role in helping cell survival and proliferation. Overexpression of heat shock proteins (HSPs) has been widely reported in human cancers and was found to correlate with tumor progression. Hepatocellular carcinoma is one of the conditions in which HSR activation was shown to have the highest clinical significance. Transcription of HSPs is induced by HSF-1, which also activates glycolytic metabolism and increases the expression of LDH-A, the master regulator of the Warburg effect. In this paper, we tried to explore the relationship between HSR and LDH-A. In cultured hepatocellular carcinoma cells, by using two enzyme inhibitors (oxamate and galloflavin), we found that the reduction of LDH-A activity led to decreased level and function of the major HSPs involved in tumorigenesis. Galloflavin (a polyphenol) also inhibited the ATPase activity of two of the examined HSPs. Finally, hindering HSR markedly lowered the alpha-fetoprotein cellular levels and induced senescence. Specific inhibitors of single HSPs are currently under evaluation in different neoplastic diseases. However, one of the effects usually observed during treatment is a compensatory elevation of other HSPs, which decreases treatment efficacy. Our results highlight a connection between LDH and HSR and suggest LDH inhibition as a way to globally impact on this tumor promoting process. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Growth inhibition and apoptosis induction by (+-Cyanidan-3-ol in hepatocellular carcinoma.

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    Jitender Monga

    Full Text Available The objective of this study was to evaluate the cytotoxicity of (+-cyanidan-3-ol (CD-3 in human hepatocellular carcinoma cell line (HepG2 and chemopreventive potential against hepatocellular carcinoma (HCC in Balb/c mice. The HepG2 cell line was treated with CD-3 at various concentrations and the proliferation of the HepG2 cells was measure by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT, sulforhodamine B (SRB and lactate dehydrogenase (LDH assays. Cell apoptosis was detected by Hoechst 33258 (HO, Acridine orange/ethylene dibromide (AO/EB staining, DNA fragmentation analysis and the apoptosis rate was detected by flow cytometry. The HCC tumor model was established in mice by injecting N-nitrosodiethylamine/carbon tetrachloride (NDEA/CCl4 and the effect of CD-3 on tumor growth in-vivo was studied. The levels of liver injury markers, tumor markers, and oxidative stress were measured. The expression levels of apoptosis-related genes in in-vitro and in vivo models were determined by RT-PCR and ELISA. The CD-3 induced cell death was considered to be apoptotic by observing the typical apoptotic morphological changes under fluorescent microscopy and DNA fragmentation analysis. Annexin V/PI assay demonstrated that apoptosis increased with increase in the concentration of CD-3. The expression levels of apoptosis-related genes that belong to bcl-2 and caspase family were increased and AP-1 and NF-κB activities were significantly suppressed by CD-3. Immunohistochemistry data revealed less localization of p53, p65 and c-jun in CD-3 treated tumors as compared to localization in NDEA/CCl4 treated tumors. Taken together, our data demonstrated that CD-3 could significantly inhibit the proliferation of HepG2 cells in-vitro and suppress HCC tumor growth in-vivo by apoptosis induction.

  1. Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3

    Institute of Scientific and Technical Information of China (English)

    Fang-Ming Gu; Quan-Lin Li; Qiang Gao; Jia-Hao Jiang; Xiao-Yong Huang; Jin-Feng Pan; Jia Fan; Jian Zhou

    2011-01-01

    AIM: To investigate the inhibitory role and the underlying mechanisms of sorafenib on signal transducer and activator of transcription 3 (STAT3) activity in hepatocellular carcinoma (HCC). METHODS: Human and rat HCC cell lines were treated with sorafenib. Proliferation and STAT3 dephosphorylation were assessed. Potential molecular mechanisms of STAT3 pathway inhibition by sorafenib were evaluated. In vivo antitumor action and STAT3 inhibition were investigated in an immunocompetent orthotopic rat HCC model. RESULTS: Sorafenib decreased STAT3 phosphorylation at the tyrosine and serine residues (Y705 and S727), but did not affect Janus kinase 2 (JAK2) and phospha-tase shatterproof 2 (SHP2), which is associated with growth inhibition in HCC cells. Dephosphorylation of S727 was associated with attenuated extracellular signal-regulated kinase (ERK) phosphorylation, similar to the effects of a mitogen-activated protein kinase (MEK) inhibitor U0126, suggesting that sorafenib induced S727 dephosphorylation by inhibiting MEK/ERK signaling. Meanwhile, sorafenib could also inhibit Akt phosphorylation, and both the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and Akt knockdown resulted in Y705 dephosphorylation, indicating that Y705 dephosphorylation by sorafenib was mediated by inhibiting the PI3K/Akt pathway. Finally, in the rat HCC model, sorafenib significantly inhibited STAT3 activity, reducing tumor growth and metastasis. CONCLUSION: Sorafenib inhibits growth and metastasis of HCC in part by blocking the MEK/ERK/STAT3 and PI3K/Akt/STAT3 signaling pathways, but independent of JAK2 and SHP2 activation.

  2. Livistona chinensis seeds inhibit hepatocellular carcinoma angiogenesis in vivo via suppression of the Notch pathway.

    Science.gov (United States)

    Lin, Wei; Zhao, Jinyan; Cao, Zhiyun; Zhuang, Qunchuan; Zheng, Liangpu; Zeng, Jianwei; Hong, Zhenfeng; Peng, Jun

    2014-04-01

    Livistona chinensis seeds have been used for centuries to clinically treat various types of cancer. Our published data suggest that Livistona chinensis seeds are able to inhibit hepatocellular carcinoma (HCC) growth in vitro and in vivo via promotion of mitochondrial-dependent apoptosis. To further elucidate the molecular mechanisms of its antitumor activity, in the present study, we used an HCC xenograft mouse model to evaluate the effect of an ethanol extract of Livistona chinensis seeds (EELC) on tumor angiogenesis and on the activation of the Notch pathway. Intratumoral microvessel density (MVD) in HCC xenograft mouse tumors was evaluated via immunohistochemical (IHC) staining for CD31. The mRNA and protein expression of vascular endothelial growth factor A (VEGF-A), VEGFR-2, Notch, Dll4 and Jagged1 was evaluated using RT-PCR and IHC, respectively. We found that EELC profoundly reduced MVD in the HCC mouse tumors, demonstrating the in vivo inhibitory effect of EELC on tumor angiogenesis. In addition, EELC treatment reduced the expression of VEGF-A and VEGFR-2 in tumor tissues. Furthermore, EELC treatment inhibited the expression of Notch, Dll4 and Jagged1. Our findings suggest that Livistona chinensis seeds inhibit tumor angiogenesis through suppression of the Notch pathway.

  3. Sulforaphane inhibits TGF-β-induced epithelial-mesenchymal transition of hepatocellular carcinoma cells via the reactive oxygen species-dependent pathway.

    Science.gov (United States)

    Wu, Jinsheng; Han, Jingli; Hou, Benxin; Deng, Chengwei; Wu, Huanliang; Shen, Liangfang

    2016-05-01

    Sulforaphane is recognized as a safe antitumor agent derived from various cruciferous vegetables, including broccoli. It has been demonstrated that sulforaphase is a potent antitumor agent in diverse cancers. However, its effect on hepatocellular carcinoma remains largely unknown. Here, we show that sulforaphane inhibits TGF-β-induced epithelial-mesenchymal transition of hepatocellular carcinoma cell via the reactive oxygen species-dependent pathway. We found sulforaphane inhibited hepatocellular carcinoma cell proliferation in a dose- and time-dependent manner. Sulforaphane induced G0/G1 phase cell cycle arrest and promoted cell apoptosis. A set of experiments showed that sulforaphase inhibited hepatocellular carcinoma cell migration and invasion, inhibited the formation of fibroblast like mesenchymal cells and the expression of Vimentin, but increased the expression of E-cadherin, suggesting sulforaphane suppresses epithelial-mesenchymal transition (EMT) process. Cotreatment with N-acetyl-L-cysteine inhibited sulforaphane-inhibited invasion and upregulation of E-cadherin and almost completely abolished the sulforaphane-induced expression of Vimentin. The effect of sulforaphane on the growth of hepatocellular carcinoma cells was confirmed by a xenograft tumor growth model. All our finding indicated that sulforaphane is a promising and safe strategy for treating hepatocellular carcinoma.

  4. RASSF1A expression inhibits cell growth and enhances cell chemosensitivity to mitomycin in BEL-7402 hepatocellular carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    GUAN Hong-geng; XUE Wan-jiang; QIAN Hai-xin; ZHOU Xiao-jun; QIN Lei; LAN Jing

    2009-01-01

    Background The antitumor role of Ras association domain family 1A (RASSFIA) gene and its potential molecular mechanisms are not well understood. The objective of this study was to observe the antitumor ability of RASSFIA in hepatoceliular carcinoma, and study the mechanisms of cell apoptosis induced by RASSFIA.Methods After stably transfecting a RASSF1A (wild-type or mutant) expression vector into the BEL-7402 hepatocellular carcinoma cell line, RT-PCR and Westem blotting was used to detect the RASSF1A expression levels in recombinant cells. The effects of wild-type RASSF1A on cell growth were observed in vitro by analyzing cell proliferation rate, cell colony formation, and in vivo by analyzing tumorigenesis in nude mice. In addition, the effect of RASSF1A gene expression on the chemosensitivity of human hepatocellular carcinoma cells to antitumor drugs was examined by inhibition of cell proliferation and the percentage of apoptotic cells.Results Wild-type RASSF1A, not the mutant, suppressed cell growth in vitro and in vivo. Re-expression of wild-type RASSF1A could enhance the inhibition of cell proliferation and the percentage of apoptotic cells following cell treatment with mitomycin, but had no significant effect when combined with adriamycin, etoposide, 5-fluorouracil and cisplatJn treatment.Conclusion Wild-type RASSF1A inhibits cell growth and enhances cell chemosensitivity to mitomycin in hepatocellular carcinoma, suggesting that RASSF1A may serve as a new target for gene therapy in hepatocellular carcinoma patients.

  5. Rho signaling inhibitor,Y-27632,inhibits invasiveness of metastastic hepatocellular carcinoma in a mouse model

    Institute of Scientific and Technical Information of China (English)

    XUE Feng; ZHANG Jian-jun; QIU Feng; ZHANG Ming; CHEN Xiao-song; LI Qi-gen; HAN Long-zhi; XI Zhi-feng; XIA Qiang

    2007-01-01

    @@ Hepatocellular carcinoma(HCC)is among the most common tumors worldwide.Despite extensive exploration of novel therapies,the prognosis of HCC patients with intrahepatic metastasis is still poor,and no treatment is effective against metastases.Therefore,more effective therapeutic strategies for treatment of metastasis are urgently needed.

  6. p19Arf Inhibits the Invasion of Hepatocellular Carcinoma Cells by Binding to CtBP

    Science.gov (United States)

    Chen, Ya-Wen; Paliwal, Seema; Draheim, Kyle; Grossman, Steven R.; Lewis, Brian C.

    2008-01-01

    The INK4A/ARF tumor suppressor locus is frequently inactivated in hepatocellular carcinoma (HCC), yet the consequences of this remain unknown. We recently described a HCC mouse model in which loss of the Ink4a/Arf locus accelerates the development of metastasis and enhances tumor cell migration and invasion in cell culture assays. We show here that knockdown of p19Arf in a HCC cell line increases invasion in cell culture assays. Further, reintroduction of p19Arf into HCC cell lines lacking Ink4a/Arf inhibits tumor cell invasion, without affecting cell proliferation, or cell transformation as measured by soft agar colony formation. Inhibition of cell invasion by p19Arf was dependent on its C-terminal binding protein (CtBP) interaction domain, but independent of Mdm2 binding and nucleolar localization. Indeed, RNAi-mediated knockdown of CtBP1 or CtBP2 decreased cell invasion, and ectopic expression of CtBP2 enhanced tumor cell migration and invasion. Thus, our data indicate a novel role for the Arf tumor suppressor protein in regulating phenotypes associated with tumor progression and metastasis in HCC cells. PMID:18199542

  7. MiR-214 inhibits cell growth in hepatocellular carcinoma through suppression of {beta}-catenin

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xiaojun [Liver Diseases Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou (China); Chen, Ji [Department of Gastrointestinal Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai (China); Li, Feng [Department of Pathology, Fujian Provincial Hospital, Fuzhou (China); Lin, Yanting [Liver Diseases Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou (China); Zhang, Xiaoping; Lv, Zhongwei [Department of Interventional Therapy, Shanghai 10th People' s Hospital, School of Medicine, Tongji University, Shanghai (China); Jiang, Jiaji, E-mail: jiang_jjcn@yahoo.com.cn [Liver Diseases Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou (China)

    2012-11-30

    Highlights: Black-Right-Pointing-Pointer miR-214 is frequently downregulated in human HCC cell lines and tissues. Black-Right-Pointing-Pointer miR-214 overexpression inhibits HCC cell growth in vitro and in vivo. Black-Right-Pointing-Pointer miR-214 directly targets {beta}-catenin 3 Prime -UTR in HCC cells. Black-Right-Pointing-Pointer miR-214 regulates {beta}-catenin downstream signaling molecules. -- Abstract: Mounting evidence has shown that microRNAs (miRNAs) are implicated in carcinogenesis and can function as oncogenes or tumor suppressor genes in human cancers. Recent profile studies of miRNA expression have documented a deregulation of miRNA (miR-214) in hepatocellular carcinoma (HCC). However, its potential functions and underlying mechanisms in hepatocarcinogenesis remain largely unknown. Here, we confirmed that miR-214 is significantly downregulated in HCC cells and specimens. Ectopic overexpression of miR-214 inhibited proliferation of HCC cells in vitro and tumorigenicity in vivo. Further studies revealed that miR-214 could directly target the 3 Prime -untranslated region (3 Prime -UTR) of {beta}-catenin mRNA and suppress its protein expression. Similar to the restoring miR-214 expression, {beta}-catenin downregulation inhibited cell growth, whereas restoring the {beta}-catenin expression abolished the function of miR-214. Moreover, miR-214-mediated reduction of {beta}-catenin resulted in suppression of several downstream genes including c-Myc, cyclinD1, TCF-1, and LEF-1. These findings indicate that miR-214 serves as tumor suppressor and plays substantial roles in inhibiting the tumorigenesis of HCC through suppression of {beta}-catenin. Given these, miR-214 may serve as a useful prognostic or therapeutic target for treatment of HCC.

  8. Luteoloside suppresses proliferation and metastasis of hepatocellular carcinoma cells by inhibition of NLRP3 inflammasome.

    Directory of Open Access Journals (Sweden)

    Shao-hua Fan

    Full Text Available The inflammasome is a multi-protein complex which when activated regulates caspase-1 activation and IL-1β secretion. Inflammasome activation is mediated by NLR proteins that respond to stimuli. Among NLRs, NLRP3 senses the widest array of stimuli. NLRP3 inflammasome plays an important role in the development of many cancer types. However, Whether NLRP3 inflammasome plays an important role in the process of hepatocellular carcinoma (HCC is still unknown. Here, the anticancer effect of luteoloside, a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, against HCC cells and the underlying mechanisms were investigated. Luteoloside significantly inhibited the proliferation of HCC cells in vitro and in vivo. Live-cell imaging and transwell assays showed that the migration and invasive capacities of HCC cells, which were treated with luteoloside, were significantly inhibited compared with the control cells. The inhibitory effect of luteoloside on metastasis was also observed in vivo in male BALB/c-nu/nu mouse lung metastasis model. Further studies showed that luteoloside could significantly reduce the intracellular reactive oxygen species (ROS accumulation. The decreased levels of ROS induced by luteoloside was accompanied by decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1. Inactivation of caspase-1 by luteoloside resulted in inhibition of IL-1β. Thus, luteoloside exerts its inhibitory effect on proliferation, invasion and metastasis of HCC cells through inhibition of NLRP3 inflammasome. Our results indicate that luteoloside can be a potential therapeutic agent not only as an adjuvant therapy for HCC, but also, in the control and prevention of metastatic HCC.

  9. Low Concentration of Caffeine Inhibits the Progression of the Hepatocellular Carcinoma via Akt Signaling Pathway.

    Science.gov (United States)

    Dong, Shuying; Kong, Jian; Kong, Jinge; Shen, Qiang; Kong, Fandong; Sun, Wenbing; Zheng, Lemin

    2015-01-01

    Accumulating evidences have reported that caffeine has anticancer effects at high blood concentrations. However, whether caffeine has anticancer effects on human hepatocellular carcinoma (HCC) cells at low concentration, especially at physiologically applicable concentration (concentrations of caffeine (0, 50, 100, 200, 400 or 600 μM). MTT assay was used to investigate the proliferation ability in vitro. Migration and invasion abilities were determined by wound healing assay and transwell assay. The molecular changes were detected by western blot. An ectopic nude mice model which the mice were gavaged with caffeine was used to reveal the anticancer effects of caffeine on HepG2 cells in vivo. Results showed that caffeine could inhibit the proliferation, migration and invasion significantly at physiologically applicable concentration in vitro. Also the associated molecular changes of cancer progression were observed. In animal experiment, the mice gavaged with caffeine also performanced reduced tumor burden in vivo. Moreover, the interrelated protein expression was also observed in vivo which was coincident with the results in vitro. All in all, this observation indicated that caffeine may suppress the progression of HCC through Akt signaling pathway. This makes caffeine a potential candidate for treating HCC which will be a safer and more effective treatment by giving for a long time at physiologically applicable concentration.

  10. Arsenite-loaded nanoparticles inhibit PARP-1 to overcome multidrug resistance in hepatocellular carcinoma cells

    Science.gov (United States)

    Liu, Hanyu; Zhang, Zongjun; Chi, Xiaoqin; Zhao, Zhenghuan; Huang, Dengtong; Jin, Jianbin; Gao, Jinhao

    2016-08-01

    Hepatocellular carcinoma (HCC) is one of the highest incidences in cancers; however, traditional chemotherapy often suffers from low efficiency caused by drug resistance. Herein, we report an arsenite-loaded dual-drug (doxorubicin and arsenic trioxide, i.e., DOX and ATO) nanomedicine system (FeAsOx@SiO2-DOX, Combo NP) with significant drug synergy and pH-triggered drug release for effective treatment of DOX resistant HCC cells (HuH-7/ADM). This nano-formulation Combo NP exhibits the synergistic effect of DNA damage by DOX along with DNA repair interference by ATO, which results in unprecedented killing efficiency on DOX resistant cancer cells. More importantly, we explored the possible mechanism is that the activity of PARP-1 is inhibited by ATO during the treatment of Combo NP, which finally induces apoptosis of HuH-7/ADM cells by poly (ADP-ribosyl) ation suppression and DNA lesions accumulation. This study provides a smart drug delivery strategy to develop a novel synergistic combination therapy for effectively overcome drug- resistant cancer cells.

  11. MicroRNA-144 inhibits hepatocellular carcinoma cell proliferation, invasion and migration by targeting ZFX

    Indian Academy of Sciences (India)

    HONGBIN BAO; XINGUO LI; HENGLI LI; HONGLI XING; BINGHUI XU; XIANFENG ZHANG; ZHAOMING LIU

    2017-03-01

    MicroRNA 144 (miR-144), a small non-coding RNA, is frequently dysregulated in human several tumour progression,but its role and the underlying mechanisms in hepatocellular carcinoma (HCC) is poorly investigated. In thepresent study, the expression of miR-144 was firstly analysed in datasets derived from GSE21362 and TCGA, andthen detected in HCC tissues and cell lines by quantitative RT-PCR (qRT-PCR) analysis. MiR-144 was shown to besignificantly down-regulated in HCC tissues and cell lines. Subsequently, overexpression of miR-144 was transfectedinto HCC cell lines so as to investigate its biological function, including MTT, colony formation, and transwell assays.Gain of function assay revealed miR-144 remarkably inhibited cell proliferation, migration and invasion. In addition,bioinformatical analysis and luciferase reporter assay identified ZFX as a novel target of miR-144 in HCC cells, asconfirmed by qRT-PCR and Western blot. Furthermore, ZFX was found to be significantly up-regulated usingOncomine database analysis. Loss of function assay further indicated knockdown of ZFX had similar effects ofmiR-144-mediated HCC cell proliferation and invasion. Therefore, miR-144 has been demonstrated to act as a tumoursuppressor in HCC cell growth and motility by directly targeting ZFX, which implicates its potential applications inthe development of HCC treatment.

  12. Growth inhibition and apoptosis induced by lupeol, a dietary triterpene, in human hepatocellular carcinoma cells.

    Science.gov (United States)

    He, Yan; Liu, Fen; Zhang, Lurong; Wu, Yan; Hu, Bo; Zhang, Yinsheng; Li, Yunsen; Liu, Haiyan

    2011-01-01

    Hepatocellular carcinoma (HCC) is the fifth most malignant tumor worldwide and is known to be resistant to conventional chemotherapy. New therapeutic strategies are urgently needed for treating HCC. Lup-20(29)-en-3H-ol (Lupeol), a novel dietary triterpene, is found in fruits, vegetables, and medicinal plants and possesses multiple bio-activities with very low toxicity. In the current study, we investigated its growth-inhibitory effects in HCC cell lines SMMC7721 and HepG2. In the in vitro studies, lupeol treatment alone caused decrease of cell viability in two HCC cell lines in a dose-dependent manner. It also induced apoptosis and caused cell accumulation in S phase. Further analysis revealed the induction of active caspase-3 and poly(ADP-ribose)polymerase (PARP) cleavage by lupeol treatment. In the in vivo studies, nude mice implanted with SMMC7721 cells subcutaneously were treated with lupeol three times a week and tumor development was significantly inhibited. We further investigated the combination anti-tumor effect of lupeol and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in HCC, considering TRAIL treatment alone could not achieve high level of anti-tumor effect. The results demonstrated that lupeol could exert a combinational effect with TRAIL, resulting in chemosensitization of HCC. Our results suggested that lupeol alone or as an adjuvant to therapeutic agents could be developed as a potential agent for treating HCC.

  13. Perspectives of TGF-β inhibition in pancreatic and hepatocellular carcinomas

    Science.gov (United States)

    Tijeras-Raballand, Annemilaï; de Mestier, Louis; Cros, Jérome; Faivre, Sandrine; Raymond, Eric

    2014-01-01

    Advanced pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) are non-curable diseases with a particularly poor prognosis. Over the last decade, research has increasingly focused on the microenvironment surrounding cancer cells, and its role in tumour development and progression. PDAC and HCC differ markedly regarding their pathological features: PDAC are typically stromal-predominant, desmoplastic, poorly vascularized tumours, whereas HCC are cellular and highly vascularized. Despite these very different settings, PDAC and HCC share transforming growth factor-β (TGF-β) as a common key-signalling mediator, involved in epithelial-to-mesenchymal transition, invasion, and stroma-tumour dialogue. Recently, novel drugs blocking the TGF-β pathway have entered clinical evaluation demonstrating activity in patients with advanced PDAC and HCC. TGF-β signalling is complex and mediates both pro- and anti-tumoural activities in cancer cells depending on their context, in space and time, and their microenvironment. In this review we provide a comprehensive overview of the role of the TGF-β pathway and its deregulation in PDAC and HCC development and progression at the cellular and microenvironment levels. We also summarize key preclinical and clinical data on the role of TGF-β as a target for therapeutic intervention in PDAC and HCC, and explore perspectives to optimize TGF-β inhibition therapy PMID:24393789

  14. Targeted inhibition of the FGF19-FGFR4 pathway in hepatocellular carcinoma; translational safety considerations.

    Science.gov (United States)

    Mellor, Howard R

    2014-07-01

    Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death and new therapies are urgently required to treat this disease. Recent data suggest that the FGF19-FGFR4 axis may be a key driver in certain forms of HCC, making the pathway an interesting, emerging molecular target for potential therapeutic intervention. A complication is that, outside of malignant disease, FGFR4 plays an important physiological role in the regulation of hepatic bile acid (BA) synthesis. FGF19 signalling via FGFR4 suppresses de novo BA production in the liver, tightly maintaining hepatic and systemic levels of these detergent-like molecules at a physiological threshold and preventing pathological complications of raised BA levels, such as cholestatic liver injury and bile acid diarrhoea. In some cases of HCC, the malignant disease causes bile duct obstruction, preventing BA secretion from the liver and resulting in cholestasis. Here, the role of FGFR4 signalling in both HCC and BA homoeostasis is discussed. The potential effects of therapeutic FGF19-FGFR4 inhibition on human hepatobiliary/gastrointestinal physiology are considered along with the potential safety implications of FGF19-FGFR4 blockade in patients with HCC.

  15. Sorafenib Enhances Radiation-Induced Apoptosis in Hepatocellular Carcinoma by Inhibiting STAT3

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Chao-Yuan [Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan (China); Department of Radiological Technology, Yuanpei University, Hsinchu, Taiwan (China); Lin, Chen-Si [School of Veterinary Medicine, National Taiwan University Hospital, Taipei, Taiwan (China); Tai, Wei-Tien; Hsieh, Chi-Ying [Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan (China); National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan (China); Shiau, Chung-Wai [Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan (China); Cheng, Ann-Lii [Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan (China); National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan (China); Chen, Kuen-Feng, E-mail: kfchen1970@ntu.edu.tw [Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan (China); National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan (China)

    2013-07-01

    Purpose: Hepatocellular carcinoma (HCC) is one of the most common and lethal human malignancies. Lack of efficient therapy for advanced HCC is a pressing problem worldwide. This study aimed to determine the efficacy and mechanism of combined sorafenib and radiation therapy treatment for HCC. Methods and Materials: HCC cell lines (PLC5, Huh-7, Sk-Hep1, and Hep3B) were treated with sorafenib, radiation, or both, and apoptosis and signal transduction were analyzed. Results: All 4 HCC cell lines showed resistance to radiation-induced apoptosis; however, this resistance could be reversed in the presence of sorafenib. Inhibition of phospho-STAT3 was found in cells treated with sorafenib or sorafenib plus radiation and subsequently reduced the expression levels of STAT3-related proteins, Mcl-1, cyclin D1, and survivin. Silencing STAT3 by RNA interference overcame apoptotic resistance to radiation in HCC cells, and the ectopic expression of STAT3 in HCC cells abolished the radiosensitizing effect of sorafenib. Moreover, sorafenib plus radiation significantly suppressed PLC5 xenograft tumor growth. Conclusions: These results indicate that sorafenib sensitizes resistant HCC cells to radiation-induced apoptosis via downregulating phosphorylation of STAT3 in vitro and in vivo.

  16. mTOR inhibition sensitizes human hepatocellular carcinoma cells to resminostat

    Energy Technology Data Exchange (ETDEWEB)

    Peng, Xingang, E-mail: pengxinggang26@sina.com [Department of Emergency General Surgery, The Affiliated Hospital of Qingdao University, Qingdao (China); Zhang, Donghui, E-mail: zhangdonghuiyx@sina.com [Department of Infectious Disease, Linyi People’s Hospital, Linyi (China); Li, Zhengling, E-mail: lizhenglingzz@sina.com [Department of Nursing, Tengzhou Central People’s Hospital, Tengzhou (China); Fu, Meili, E-mail: fumeilidrlinyi@tom.com [Department of Infectious Disease, Linyi People’s Hospital, Linyi (China); Liu, Haiyan, E-mail: liuhaiyanlinyi5@sina.com [Department of Nursing, Linyi People’s Hospital, Linyi (China)

    2016-09-02

    Histone deacetylases (HDACs) hyper-activity in hepatocellular carcinoma (HCC) is often associated with patients’ poor prognosis. Our previous study has shown that resminostat, a novel HDAC inhibitor (HDACi), activated mitochondrial permeability transition pore (mPTP)-dependent apoptosis pathway in HCC cells. Here we explored the potential resminostat resistance factor by focusing on mammalian target of rapamycin (mTOR). We showed that AZD-2014, a novel mTOR kinase inhibitor, potentiated resminostat-induced cytotoxicity and proliferation inhibition in HCC cells. Molecularly, AZD-2014 enhanced resminostat-induced mPTP apoptosis pathway activation in HCC cells. Inhibition of this apoptosis pathway, by the caspase-9 specific inhibitor Ac-LEHD-CHO, the mPTP blockers (sanglifehrin A/cyclosporine A), or by shRNA-mediated knockdown of mPTP component cyclophilin-D (Cyp-D), significantly attenuated resminostat plus AZD-2014-induced cytotoxicity and apoptosis in HCC cells. Significantly, mTOR shRNA knockdown or kinase-dead mutation (Asp-2338-Ala) also sensitized HCC cells to resminostat, causing profound cytotoxicity and apoptosis induction. Together, these results suggest that mTOR could be a primary resistance factor of resminostat. Targeted inhibition of mTOR may thus significantly sensitize HCC cells to resminostat. - Highlights: • AZD-2014 potentiates resminostat’s cytotoxicity against HCC cells. • AZD-2014 facilitates resminostat-induced HCC cell apoptosis. • AZD-2014 augments resminostat-induced mitochondrial apoptosis pathway activation. • mTOR shRNA or kinase-dead mutation significantly sensitizes HCC cells to resminostat.

  17. Retinoic acid and cAMP inhibit rat hepatocellular carcinoma cell proliferation and enhance cell differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Ionta, M. [Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas MG (Brazil); Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo SP (Brazil); Rosa, M.C.; Almeida, R.B.; Freitas, V.M.; Rezende-Teixeira, P.; Machado-Santelli, G.M. [Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo SP (Brazil)

    2012-05-25

    Hepatocellular carcinoma (HCC) is the third highest cause of cancer death worldwide. In general, the disease is diagnosed at an advanced stage when potentially curative therapies are no longer feasible. For this reason, it is very important to develop new therapeutic approaches. Retinoic acid (RA) is a natural derivative of vitamin A that regulates important biological processes including cell proliferation and differentiation. In vitro studies have shown that RA is effective in inhibiting growth of HCC cells; however, responsiveness to treatment varies among different HCC cell lines. The objective of the present study was to determine if the combined use of RA (0.1 µM) and cAMP (1 mM), an important second messenger, improves the responsiveness of HCC cells to RA treatment. We evaluated the proliferative behavior of an HCC cell line (HTC) and the expression profile of genes related to cancer signaling pathway (ERK and GSK-3β) and liver differentiation [E-cadherin, connexin 26 (Cx26), and connexin 32 (Cx32)]. RA and cAMP were effective in inhibiting the proliferation of HTC cells independently of combined use. However, when a mixture of RA and cAMP was used, the signals concerning the degree of cell differentiation were increased. As demonstrated by Western blot, the treatment increased E-cadherin, Cx26, Cx32 and Ser9-GSK-3β (inactive form) expression while the expression of Cx43, Tyr216-GSK-3β (active form) and phosphorylated ERK decreased. Furthermore, telomerase activity was inhibited along treatment. Taken together, the results showed that the combined use of RA and cAMP is more effective in inducing differentiation of HTC cells.

  18. Dominant Suppression of β1 Integrin by Ectopic CD98-ICD Inhibits Hepatocellular Carcinoma Progression

    Directory of Open Access Journals (Sweden)

    Bo Wu

    2016-11-01

    Full Text Available Hepatocellular carcinoma (HCC is currently the third most common cause of cancer-related death in the Asia-Pacific region. Our previous work showed that knockdown of CD98 significantly inhibits malignant HCC cell phenotypes in vitro and in vivo. The level of CD98 in the membrane is tightly regulated to mediate complex processes associated with cell–cell communication and intracellular signaling. In addition, the intracellular domain of CD98 (CD98-ICD seems to be of vital importance for recycling CD98 to the membrane after it is endocytosed. The intracellular and transmembrane domains of CD98 associate with β-integrins (primarily β1 but also β3, and this association is essential for CD98 mediation of integrin-like signaling and complements dominant suppression of β1-integrin. We speculated that isolated CD98-ICD would similarly suppress β1-integrin activation and inhibit the malignant behaviors of cancer cells. In particular, the exact role of CD98-ICD has not been studied independently in HCC. In this study, we found that ectopic expression of CD98-ICD inhibited the malignant phenotypes of HCC cells, and the mechanism possibly involves β1-integrin suppression. Moreover, the expression levels of CD98, β1-integrin-A (the activated form of β1-integrin and Ki-67 were significantly increased in HCC tissues relative to those of normal liver tissues. Therefore, our preliminary study indicates that ectopic CD98-ICD has an inhibitory role in the malignant development of HCC, and shows that CD98-ICD acts as a dominant negative mutant of CD98 that attenuates β1-integrin activation. CD98-ICD may emerge as a promising candidate for antitumor treatment.

  19. Tumor suppressor and hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Juliette Martin; Jean-Frangois Dufour

    2008-01-01

    A few signaling pathways are driving the growth of hepatocellular carcinoma. Each of these pathways possesses negative regulators. These enzymes, which normally suppress unchecked cell proliferation, are circumvented in the oncogenic process, either the over-activity of oncogenes is sufficient to annihilate the activity of tumor suppressors or tumor suppressors have been rendered ineffective. The loss of several key tumor suppressors has been described in hepatocellular carcinoma. Here, we systematically review the evidence implicating tumor suppressors in the development of hepatocellular carcinoma.

  20. Growth inhibition and apoptosis induced by osthole, a natural coumarin, in hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Lurong Zhang

    Full Text Available BACKGROUND: Hepatocellular carcinoma (HCC is one of the most commonly diagnosed tumors worldwide and is known to be resistant to conventional chemotherapy. New therapeutic strategies are urgently needed for treating HCC. Osthole, a natural coumarin derivative, has been shown to have anti-tumor activity. However, the effects of osthole on HCC have not yet been reported. METHODS AND FINDINGS: HCC cell lines were treated with osthole at various concentrations for 24, 48 and 72 hours. The proliferations of the HCC cells were measured by MTT assays. Cell cycle distribution and apoptosis were determined by flow cytometry. HCC tumor models were established in mice by subcutaneously injection of SMMC-7721 or Hepa1-6 cells and the effect of osthole on tumor growths in vivo and the drug toxicity were studied. NF-κB activity after osthole treatment was determined by electrophoretic mobility shift assays and the expression of caspase-3 was measured by western blotting. The expression levels of other apoptosis-related genes were also determined by real-time PCR (PCR array assays. Osthole displayed a dose- and time-dependent inhibition of the HCC cell proliferations in vitro. It also induced apoptosis and caused cell accumulation in G2 phase. Osthole could significantly suppress HCC tumor growth in vivo with no toxicity at the dose we used. NF-κB activity was significantly suppressed by osthole at the dose- and time-dependent manner. The cleaved caspase-3 was also increased by osthole treatment. The expression levels of some apoptosis-related genes that belong to TNF ligand family, TNF receptor family, Bcl-2 family, caspase family, TRAF family, death domain family, CIDE domain and death effector domain family and CARD family were all increased with osthole treatment. CONCLUSION: Osthole could significantly inhibit HCC growth in vitro and in vivo through cell cycle arrest and inducing apoptosis by suppressing NF-κB activity and promoting the expressions of

  1. Growth Inhibition and Apoptosis Induced by Osthole, A Natural Coumarin, in Hepatocellular Carcinoma

    Science.gov (United States)

    Zhang, Lurong; Jiang, Guorong; Yao, Fei; He, Yan; Liang, Guoqiang; Zhang, Yinsheng; Hu, Bo; Wu, Yan; Li, Yunsen; Liu, Haiyan

    2012-01-01

    Background Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed tumors worldwide and is known to be resistant to conventional chemotherapy. New therapeutic strategies are urgently needed for treating HCC. Osthole, a natural coumarin derivative, has been shown to have anti-tumor activity. However, the effects of osthole on HCC have not yet been reported. Methods and Findings HCC cell lines were treated with osthole at various concentrations for 24, 48 and 72 hours. The proliferations of the HCC cells were measured by MTT assays. Cell cycle distribution and apoptosis were determined by flow cytometry. HCC tumor models were established in mice by subcutaneously injection of SMMC-7721 or Hepa1-6 cells and the effect of osthole on tumor growths in vivo and the drug toxicity were studied. NF-κB activity after osthole treatment was determined by electrophoretic mobility shift assays and the expression of caspase-3 was measured by western blotting. The expression levels of other apoptosis-related genes were also determined by real-time PCR (PCR array) assays. Osthole displayed a dose- and time-dependent inhibition of the HCC cell proliferations in vitro. It also induced apoptosis and caused cell accumulation in G2 phase. Osthole could significantly suppress HCC tumor growth in vivo with no toxicity at the dose we used. NF-κB activity was significantly suppressed by osthole at the dose- and time-dependent manner. The cleaved caspase-3 was also increased by osthole treatment. The expression levels of some apoptosis-related genes that belong to TNF ligand family, TNF receptor family, Bcl-2 family, caspase family, TRAF family, death domain family, CIDE domain and death effector domain family and CARD family were all increased with osthole treatment. Conclusion Osthole could significantly inhibit HCC growth in vitro and in vivo through cell cycle arrest and inducing apoptosis by suppressing NF-κB activity and promoting the expressions of apoptosis

  2. Silybin-mediated inhibition of Notch signaling exerts antitumor activity in human hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Song Zhang

    Full Text Available Hepatocellular carcinoma (HCC is a global health burden that is associated with limited treatment options and poor patient prognoses. Silybin (SIL, an antioxidant derived from the milk thistle plant (Silybum marianum, has been reported to exert hepatoprotective and antitumorigenic effects both in vitro and in vivo. While SIL has been shown to have potent antitumor activity against various types of cancer, including HCC, the molecular mechanisms underlying the effects of SIL remain largely unknown. The Notch signaling pathway plays crucial roles in tumorigenesis and immune development. In the present study, we assessed the antitumor activity of SIL in human HCC HepG2 cells in vitro and in vivo and explored the roles of the Notch pathway and of the apoptosis-related signaling pathway on the activity of SIL. SIL treatment resulted in a dose- and time-dependent inhibition of HCC cell viability. Additionally, SIL exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration, intracellular glutathione (GSH levels and total antioxidant capability (T-AOC but also by increases in the apoptotic index, caspase3 activity, and reactive oxygen species (ROS. Furthermore, SIL treatment decreased the expression of the Notch1 intracellular domain (NICD, RBP-Jκ, and Hes1 proteins, upregulated the apoptosis pathway-related protein Bax, and downregulated Bcl2, survivin, and cyclin D1. Notch1 siRNA (in vitro or DAPT (a known Notch1 inhibitor, in vivo further enhanced the antitumor activity of SIL, and recombinant Jagged1 protein (a known Notch ligand in vitro attenuated the antitumor activity of SIL. Taken together, these data indicate that SIL is a potent inhibitor of HCC cell growth that targets the Notch signaling pathway and suggest that the inhibition of Notch signaling may be a novel therapeutic intervention for HCC.

  3. Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Johannes Klose

    Full Text Available Salinomycin raised hope to be effective in anti-cancer therapies due to its capability to overcome apoptosis-resistance in several types of cancer cells. Recently, its effectiveness against human hepatocellular carcinoma (HCC cells both in vitro and in vivo was demonstrated. However, the mechanism of action remained unclear. Latest studies implicated interference with the degradation pathway of autophagy. This study aimed to determine the impact of Salinomycin on HCC-autophagy and whether primary human hepatocytes (PHH likewise are affected. Following exposure of HCC cell lines HepG2 and Huh7 to varying concentrations of Salinomycin (0-10 µM, comprehensive analysis of autophagic activity using western-blotting and flow-cytometry was performed. Drug effects were analyzed in the settings of autophagy stimulation by starvation or PP242-treatment and correlated with cell viability, proliferation, apoptosis induction, mitochondrial mass accumulation and reactive oxygen species (ROS formation. Impact on apoptosis induction and cell function of PHH was analyzed. Constitutive and stimulated autophagic activities both were effectively suppressed in HCC by Salinomycin. This inhibition was associated with dysfunctional mitochondria accumulation, increased apoptosis and decreased proliferation and cell viability. Effects of Salinomycin were dose and time dependent and could readily be replicated by pharmacological and genetic inhibition of HCC-autophagy alone. Salinomycin exposure to PHH resulted in transient impairment of synthesis function and cell viability without apoptosis induction. In conclusion, our data suggest that Salinomycin suppresses late stages of HCC-autophagy, leading to impaired recycling and accumulation of dysfunctional mitochondria with increased ROS-production all of which are associated with induction of apoptosis.

  4. Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells.

    Science.gov (United States)

    Klose, Johannes; Stankov, Metodi V; Kleine, Moritz; Ramackers, Wolf; Panayotova-Dimitrova, Diana; Jäger, Mark D; Klempnauer, Jürgen; Winkler, Michael; Bektas, Hüseyin; Behrens, Georg M N; Vondran, Florian W R

    2014-01-01

    Salinomycin raised hope to be effective in anti-cancer therapies due to its capability to overcome apoptosis-resistance in several types of cancer cells. Recently, its effectiveness against human hepatocellular carcinoma (HCC) cells both in vitro and in vivo was demonstrated. However, the mechanism of action remained unclear. Latest studies implicated interference with the degradation pathway of autophagy. This study aimed to determine the impact of Salinomycin on HCC-autophagy and whether primary human hepatocytes (PHH) likewise are affected. Following exposure of HCC cell lines HepG2 and Huh7 to varying concentrations of Salinomycin (0-10 µM), comprehensive analysis of autophagic activity using western-blotting and flow-cytometry was performed. Drug effects were analyzed in the settings of autophagy stimulation by starvation or PP242-treatment and correlated with cell viability, proliferation, apoptosis induction, mitochondrial mass accumulation and reactive oxygen species (ROS) formation. Impact on apoptosis induction and cell function of PHH was analyzed. Constitutive and stimulated autophagic activities both were effectively suppressed in HCC by Salinomycin. This inhibition was associated with dysfunctional mitochondria accumulation, increased apoptosis and decreased proliferation and cell viability. Effects of Salinomycin were dose and time dependent and could readily be replicated by pharmacological and genetic inhibition of HCC-autophagy alone. Salinomycin exposure to PHH resulted in transient impairment of synthesis function and cell viability without apoptosis induction. In conclusion, our data suggest that Salinomycin suppresses late stages of HCC-autophagy, leading to impaired recycling and accumulation of dysfunctional mitochondria with increased ROS-production all of which are associated with induction of apoptosis.

  5. Genistein inhibits invasive potential of human hepatocellular carcinoma by altering cell cycle, apoptosis, and angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Yan Gu; Chen-Fang Zhu; Hitoshi Iwamoto; Ji-Sheng Chen

    2005-01-01

    AIM: To study the in vitro and in vivo inhibitory effects of genistein on invasive potential of Bel 7402 hepatocellular carcinoma (HCC) cells and to explore the underlying mechanism.METHODS: Bel 7402 HCC cells were exposed to genistein. The invasive activity of tumor cells was assayed in transwell cell culture chamber. p125FAK expression and cell cycle were evaluated by a functional assay. Cell apoptosis analysis was performed with TUNEL method. In addition, bilateral subrenal capsule xenograft transplantation of HCC was performed in 10 nude mice.Genistein was injected and the invasion of HCC into the renal parenchyma was observed. Microvessels with immunohistochemical staining were detected.RESULTS: Genistein significantly inhibited the growth of Bel 7402 cells, the inhibitory rate of tumor cells was 26 -42%. The invasive potential of Bel 7402 cells in vitro was significantly inhibited, the inhibitory rate was 11-28%. Genistein caused G2/M cell cycle arrest, S phase decreased significantly. The occurrence of apoptosis in genistein group increased significantly. The expression of p125FAK in 5 μg/mL genistein group (15.26±0.16%)and 10 μg/mL genistein group (12.89±0.36%) was significantly lower than that in the control group (19.75± 1.12%,P<0.05). Tumor growth in genistein-treated nude mice was significantly retarded in comparison to control mice, the inhibitory rate of tumor growth was about 20%. Genistein also significantly inhibited the invasion of Bel 7402 cells into the renal parenchyma of nude mice with xenograft transplant. The positive unit value of microvessels in genistein-treated group (10.422±0.807)was significantly lower than that in control group (22.330 ± 5.696, P< 0.01).CONCLUSION: Genistein can effectively inhibit the invasive potential of Bel 7402 HCC cells by altering cell cycle, apoptosis and angiogenesis, inhibition of focal adhesion kinase may play a significant role in this process.

  6. Cryotherapy for hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Awad, Tahany; Thorlund, Kristian; Gluud, Christian

    2009-01-01

    for the treatment of hepatocellular carcinoma. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and LILACS until June 2009. We identified further studies by searching...... national and topic-specific databases, bibliographies, conference abstracts, journals, and grey literature. Furthermore, we reviewed the reference lists and contacted the principal authors of the identified studies. SELECTION CRITERIA: Randomised clinical trials (irrespective of language or publication...

  7. Salinomycin inhibits proliferation and induces apoptosis of human hepatocellular carcinoma cells in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Fan Wang

    Full Text Available The anti-tumor antibiotic salinomycin (Sal was recently identified as a selective inhibitor of breast cancer stem cells; however, the effect of Sal on hepatocellular carcinoma (HCC is not clear. This study aimed to determine the anti-tumor efficacy and mechanism of Sal on HCC. HCC cell lines (HepG2, SMMC-7721, and BEL-7402 were treated with Sal. Cell doubling time was determinated by drawing growth curve, cell viability was evaluated using the Cell Counting Kit 8. The fraction of CD133(+ cell subpopulations was assessed by flow cytometry. We found that Sal inhibits proliferation and decreases PCNA levels as well as the proportion of HCC CD133(+cell subpopulations in HCC cells. Cell cycle was analyzed using flow cytometry and showed that Sal caused cell cycle arrest of the various HCC cell lines in different phases. Cell apoptosis was evaluated using flow cytometry and Hoechst 33342 staining. Sal induced apoptosis as characterized by an increase in the Bax/Bcl-2 ratio. Several signaling pathways were selected for further mechanistic analyses using real time-PCR and Western blot assays. Compared to control, β-catenin expression is significantly down-regulated upon Sal addition. The Ca(2+ concentration in HCC cells was examined by flow cytometry and higher Ca(2+ concentrations were observed in Sal treatment groups. The anti-tumor effect of Sal was further verified in vivo using the hepatoma orthotopic tumor model and the data obtained showed that the size of liver tumors in Sal-treated groups decreased compared to controls. Immunohistochemistry and TUNEL staining also demonstrated that Sal inhibits proliferation and induces apoptosis in vivo. Finally, the role of Sal on in vivo Wnt/β-catenin signaling was evaluated by Western blot and immunohistochemistry. This study demonstrates Sal inhibits proliferation and induces apoptosis of HCC cells in vitro and in vivo and one potential mechanism is inhibition of Wnt/β-catenin signaling via increased

  8. 4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to inhibit hepatocellular carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Meili, E-mail: fumeilidrlinyi@tom.com [Department of Infectious Disease, Linyi People' s Hospital, Linyi 276000 (China); Wan, Fuqiang [Department of Head and Neck Surgery, Linyi Tumor Hospital, Linyi 276000 (China); Li, Zhengling [Department of Nursing, Tengzhou Central People' s Hospital, Tengzhou 277500 (China); Zhang, Fenghua [Department of Operating Room, Linyi People' s Hospital, Linyi 276000 (China)

    2016-03-04

    The aim of the present study is to investigate the potential anti-hepatocellular carcinoma (HCC) cell activity by 4SC-202, a novel class I HDAC inhibitor (HDACi). The associated signaling mechanisms were also analyzed. We showed that 4SC-202 treatment induced potent cytotoxic and proliferation–inhibitory activities against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Further, adding 4SC-202 in HCC cells activated mitochondrial apoptosis pathway, which was evidenced by mitochondrial permeability transition pore (mPTP) opening, cytochrome C cytosol release and caspase-3/-9 activation. Inhibition of this apoptosis pathway, by caspase-3/-9 inhibitors, mPTP blockers, or by shRNA-mediated knockdown of cyclophilin-D (Cyp-D, a key component of mPTP), significantly attenuated 4SC-202-induced HCC cell death and apoptosis. Reversely, over-expression of Cyp-D enhanced 4SC-202's sensitivity in HCC cells. Further studies showed that 4SC-202 induced apoptosis signal-regulating kinase 1 (ASK1) activation, causing it translocation to mitochondria and physical association with Cyp-D. This mitochondrial ASK1-Cyp-D complexation appeared required for mediating 4SC-202-induced apoptosis activation. ASK1 stable knockdown by targeted-shRNAs largely inhibited 4SC-202-induced mPTP opening, cytochrome C release, and following HCC cell apoptotic death. Together, we suggest that 4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to potently inhibit human HCC cells. - Highlights: • 4SC-202 exerts potent anti-proliferative and cytotoxic activity against established/primary HCC cells. • SC-202-induced anti-HCC cell activity relies on caspase-dependent apoptosis activation. • 4SC-202 activates Cyp-D-dependent mitochondrial apoptosis pathway in HCC cells. • 4SC-202 activates ASK1 in HCC cells, causing it translocation to mitochondria. • Mitochondrial ASK1-Cyp-D complexation mediates 4SC-202's activity in HCC cells.

  9. Cyclooxygenases in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Melchiorre Cervello; Giuseppe Montalto

    2006-01-01

    Many epidemiological studies demonstrate that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) reduce the incidence and mortality of certain malignancies, especially gastrointestinal cancer. The cyclooxygenase (COX) enzymes are well-known targets of NSAIDs. However, conventional NSAIDs nonselectively inhibit both the constitutive form COX-1, and the inducible form COX-2. Recent evidence indicates that COX-2 is an important molecular target for anticancer therapies. Its expression is undetectable in most normal tissues, and is highly induced by proinflammatory cytokines, mitogens, tumor promoters and growth factors. It is now well-established that COX-2 is chronically overexpressed in many premalignant, malignant, and metastastic cancers, including hepatocellular carcinoma (HCC). Overexpression of COX-2 in patients with HCC is generally higher in welldifferentiated HCCs compared with less-differentiated HCCs or histologically normal liver, suggesting that COX-2 may be involved in the early stages of hepatocarcinogenesis, and increased expression of COX-2 in noncancerous liver tissue has been significantly associated with shorter disease-free survival in patients with HCC.In tumors, overexpression of COX-2 leads to an increase in prostaglandin (PG) levels, which affect many mechanisms involved in carcinogenesis, such as angiogenesis, inhibition of apoptosis, stimulation of cell growth as well as the invasiveness and metastatic potential of tumor ceils. The availability of novel agents that selectively inhibit COX-2 (COXIB), has contributed to shedding light on the role of this molecule. Experimental studies on animal models of liver cancer have shown that NSAIDs, including both selective and non-selective COX-2 inhibitors, exert chemopreventive as well as therapeutic effects. However, the key mechanism by which COX-2 inhibitors affect HCC cell growth is as yet not fully understood. Increasing evidence suggests the involvement of molecular targets other

  10. MicroRNA-133b inhibits hepatocellular carcinoma cell progression by targeting Sirt1.

    Science.gov (United States)

    Tian, Zhijie; Jiang, Hequn; Liu, Ying; Huang, Yong; Xiong, Xin; Wu, Hongwei; Dai, Xiaozhen

    2016-05-01

    MicroRNAs (miRNAs) are a class of small non-coding RNAs that function as critical gene regulators by targeting mRNAs for translational repression or degradation. In this study, we showed that the expression level of miR-133b was decreased, while Sirt1 mRNA expression levels were increased in hepatocellular carcinoma (HCC) and cell lines, and we identified Sirt1 as a novel direct target of miR-133b. The over-expression of miR-133b suppressed Sirt1 expression. In addition, miR-133b over-expression resulted in attenuating HCC cell proliferation and invasion together with apoptosis increase in vitro. HepG2 cell transplantation revealed that up-regulation of miR-133b could inhibit HCC tumor genesis in vivo. Forced expression of Sirt1 partly rescued the effect of miR-133b in vitro. Furthermore, our study showed that miR-133b over-expression or Sirt1 down-regulation elevated E-cadherin expression, and repressed glypican-3 (GPC3) and the anti-apoptotic proteins (Bcl-2, Bcl-xL, and Mcl-1) expression. The inhibition of GPC3 expression repressed Bcl-2, Bcl-xL, and Mcl-1 expression, and elevated E-cadherin expression. Moreover, the Sirt1 up-regulation resulted in increases in HCC cell proliferation and invasion together with decreases apoptosis, and increases in the cytosolic accumulation and nuclear translocation of the transcription factor β-catenin in vitro. But the effect of Sirt1 up-regulation was partly reversed by GPC3 down-regulation in vitro. Taken together, these findings provide insight into the role and mechanism of miR-133b in regulating HCC cell proliferation, invasion and apoptosis via the miR-133b/Sirt1/GPC3/Wnt β-catenin axis, and miR-133b may serve as a potential therapeutic target in HCC in the future.

  11. By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma.

    Science.gov (United States)

    Li, Sainan; Dai, Weiqi; Mo, Wenhui; Li, Jingjing; Feng, Jiao; Wu, Liwei; Liu, Tong; Yu, Qiang; Xu, Shizan; Wang, Wenwen; Lu, Xiya; Zhang, Qinghui; Chen, Kan; Xia, Yujing; Lu, Jie; Zhou, Yingqun; Fan, Xiaoming; Xu, Ling; Guo, Chuanyong

    2017-08-31

    Hepatocellular carcinoma (HCC) is one of the few cancers with a continuous increase in incidence and mortality. Drug resistance is a major problem in the treatment of HCC. In this study, two sorafenib-resistant HCC cell lines and a nude mouse subcutaneously tumor model were used to explore the possible mechanisms leading to sorafenib resistance, and to investigate whether aspirin could increase the sensitivity of hepatoma cells to sorafenib. The combination of aspirin and sorafenib resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. High glycolysis and PFKFB3 overexpression occupied a dominant position in sorafenib resistance, and can be targeted and overcome by aspirin. Aspirin plus sorafenib induced apoptosis in tumors without inducing weight loss, hepatotoxicity or inflammation. Our results suggest that aspirin overcomes sorafenib resistance and their combination may be an effective treatment approach for HCC. © 2017 UICC.

  12. Asparagus polysaccharide and gum with hepatic artery embolization induces tumor growth and inhibits angiogenesis in an orthotopic hepatocellular carcinoma model.

    Science.gov (United States)

    Weng, Ling-Ling; Xiang, Jian-Feng; Lin, Jin-Bo; Yi, Shang-Hui; Yang, Li-Tao; Li, Yi-Sheng; Zeng, Hao-Tao; Lin, Sheng-Ming; Xin, Dong-Wei; Zhao, Hai-Liang; Qiu, Shu-Qi; Chen, Tao; Zhang, Min-Guang

    2014-01-01

    Liver cancer is one of leading digestive malignancies with high morbidity and mortality. There is an urgent need for the development of novel therapies for this deadly disease. It has been proven that asparagus polysaccharide, one of the most active derivates from the traditional medicine asparagus, possesses notable antitumor properties. However, little is known about the efficacy of asparagus polysaccharide as an adjuvant for liver cancer chemotherapy. Herein, we reported that asparagus polysaccharide and its embolic agent form, asparagus gum, significantly inhibited liver tumor growth with transcatheter arterial chemoembolization (TACE) therapy in an orthotopic hepatocellular carcinoma (HCC) tumor model, while significantly inhibiting angiogenesis and promoting tumor cell apoptosis. Moreover, asparagine gelatinous possessed immunomodulatory functions and showed little toxicity to the host. These results highlight the chemotherapeutic potential of asparagus polysaccharide and warrant a future focus on development as novel chemotherapeutic agent for liver cancer TACE therapy.

  13. Cutaneous metastases of hepatocellular carcinoma.

    Science.gov (United States)

    Lazaro, M; Serrano, M L; Allende, I; Ratón, J A; Acebo, E; Diaz-Perez, J L

    2009-12-01

    Cutaneous metastases are an unusual finding that may present as the first sign of an internal neoplasia. A case of cutaneous metastases of hepatocellular carcinoma, which may often involve other organs but very rarely metastases to the skin, is reported.

  14. Surgery and Hepatocellular Carcinoma

    Science.gov (United States)

    Akamatsu, Nobuhisa; Cillo, Umberto; Cucchetti, Alessandro; Donadon, Matteo; Pinna, Antonio Daniele; Torzilli, Guido; Kokudo, Norihiro

    2016-01-01

    The optimal surgical strategy for hepatocellular carcinoma (HCC) is under active debate. Bio-markers of the liver functional reserve as well as volumetric analysis of the future liver remnant are essential for safe liver resection of HCC. The present algorithms applied to surgical strategies for HCC are not ideal because many patients who could potentially undergo safe resection are deemed liver transplant candidates in Western countries, whereas the opposite is the case in Eastern countries. In addition, there is too much focus on expanded criteria for patients with HCC to undergo liver transplantation. The transplantation benefit for patients with HCC should be considered based not only on the individual's benefit, but also on the effect of other patients waiting for LT for other indications. PMID:27995087

  15. Hepatocellular Carcinoma (HCC)

    Science.gov (United States)

    Helmberger, Thomas K.

    Hepatocellular carcinoma (HCC) is considered to be one of the most common malignancies worldwide, and the most common one in Africa and Asia. Over the last decade, a rising incidence of up to 10-15/100,000 per population has been seen in the Western world, with an estimate of 250,000 deaths and more than a million worldwide per year. By the year 2010, the World Health Organization expects that HCC will be the leading cause of cancer mortality surpassing lung cancer. This increasing incidence is most likely related to an increasing prevalence of chronic hepatitis C (HC) and B (HB) virus infections and other diseases inducing chronic inflammation (Befeler and Di Bisceglie 2002; Llovet et al. 2003).

  16. Thrombocytosis and hepatocellular carcinoma.

    Science.gov (United States)

    Carr, Brian I; Guerra, Vito

    2013-06-01

    Thrombocytopenia has been reported to be both a risk factor for hepatocellular carcinoma (HCC) development as well as a prognostic factor. Many HCCs also occur in presence of normal platelets. To examine a cohort of HCC patients with associated thrombocytosis. Records were examined of a cohort of 634 biopsy-proven and randomly presenting HCC patients without thrombocytopenia. In the total cohort, 52 patients were identified with thrombocytosis (platelet levels >400 × 10(9)/L) and compared with 582 patients with normal platelet values. The average tumor sizes were 13.1 versus 8.8 cm (p thrombocytosis patients versus normal platelet count HCC patients. These differences were even more pronounced in patients with HCC sizes >5 cm. Thrombocytosis patients were younger and had less cirrhosis, but similar percent with hepatitis B or C or alcohol consumption. Thrombocytosis in association with HCC occurs in patients with larger tumor sizes and better liver function.

  17. Genetics of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Andreas Teufel; Frank Staib; Stephan Kanzler; Arndt Weinmann; Henning Schulze-Bergkamen; Peter R Galle

    2007-01-01

    The completely assembled human genome has made it possible for modern medicine to step into an era rich in genetic information and high-throughput genomic analysis. These novel and readily available genetic resources and analytical tools may be the key to unravel the molecular basis of hepatocellular carcinoma (HCC). Moreover, since an efficient treatment for this disease is lacking, further understanding of the genetic background of HCC will be crucial in order to develop new therapies aimed at selected targets. We report on the current status and recent developments in HCC genetics. Special emphasis is given to the genetics and regulation of major signalling pathways involved in HCC such as p53, Wntsignalling, TGFβ, Ras, and Rb pathways. Furthermore, we describe the influence of chromosomal aberrations as well as of DNA methylation. Finally, we report on the rapidly developing field of genomic expression profiling in HCC, mainly by microarray analysis.

  18. Non-toxic dose of liposomal honokiol suppresses metastasis of hepatocellular carcinoma through destabilizing EGFR and inhibiting the downstream pathways

    Science.gov (United States)

    Yang, Hansuo; Hu, Jia; Zhao, Chengjian; Chai, LuLu; Chen, Xiang; Shao, Ximing; Wang, Chunyu; Wu, Wenshuang; Wan, Li; Ye, Haoyu; Qiu, Qiang; Peng, Aihua; Wei, Yuquan; Yang, Li; Chen, Lijuan

    2017-01-01

    At present, there is no specific anti-metastasis drug in HCC treatment. Drugs used for primary HCC tumors and tumor metastasis are very similar, among which cytotoxic drugs are prevalent, such as cisplatin, doxorubicin and 5-FU. The EGFR pathway plays an important role in promoting hepatocellular carcinoma (HCC) metastasis. Hence, development of non-toxic anti-metastasis drugs, such as EGFR or downstream pathways inhibitors, is of great importance. In our present study, we found non-toxic dose of liposomal honokiol (LH) could inhibit the HCC metastasis by destabilizing EGFR and inhibiting the downstream pathways. Non-toxic dose of LH significantly inhibited the motility, migration and lamellipodia formation of HepG2 cells in vitro and decreased extravasation of HepG2 cells in a novel metastasis model of transgenic zebrafish. In two lung metastasis models (HepG2 and B16F10) and a spontaneous metastasis model of HepG2 cells, LH remarkably inhibited pulmonary metastasis and regional lymph nodes metastasis without obvious toxicity. Further study showed that destabilizing EGFR and inhibiting the downstream pathways were the main mechanisms of non-toxic dose of LH on metastasis inhibition. Our results provide the preclinical rationale and the underlying mechanisms of LH to suppress HCC metastasis, implicating LH as a potential therapeutic agent to block HCC metastasis without severe side effects. PMID:27906672

  19. Over Expression of Long Non-Coding RNA PANDA Promotes Hepatocellular Carcinoma by Inhibiting Senescence Associated Inflammatory Factor IL8.

    Science.gov (United States)

    Peng, Chuanhui; Hu, Wendi; Weng, Xiaoyu; Tong, Rongliang; Cheng, Shaobing; Ding, Chaofeng; Xiao, Heng; Lv, Zhen; Xie, Haiyang; Zhou, Lin; Wu, Jian; Zheng, Shusen

    2017-06-23

    It has been reported that long non-coding RNA PANDA was disregulated in varieties types of tumor, but its expression level and biological role in hepatocellular carcinoma (HCC) remains contradictory. We detected PANDA expression in two independent cohorts (48 HCC patients following liver transplantation and 84 HCC patients following liver resection), and found that PANDA was down-regulated in HCC. Thereafter we explored its function in cancer biology by inversing its low expression. Surprisingly, overexpression of PANDA promoted HCC proliferation and carcinogenesis in vitro and in vivo. Mechanistically, PANDA repressed transcriptional activity of senescence associated inflammatory factor IL8, which leaded to inhibition of cellular senescence. Therefore, our research help to better understand the complex role of PANDA in HCC, and suggest more thoughtful strategies should be applied before it can be treated as a potential therapeutic target.

  20. Metformin inhibits the prometastatic effect of sorafenib in hepatocellular carcinoma by upregulating the expression of TIP30.

    Science.gov (United States)

    Guo, Zhigui; Cao, Manqing; You, Abin; Gao, Junrong; Zhou, Hongyuan; Li, Huikai; Cui, Yunlong; Fang, Feng; Zhang, Wei; Song, Tianqiang; Li, Qiang; Zhu, Xiaolin; Sun, Huichuan; Zhang, Ti

    2016-04-01

    We previously found that a low dose of sorafenib had a prometastatic effect on hepatocellular carcinoma (HCC), which was caused by downregulation of TIP30 expression. More recently, metformin has been shown to have potential as a preventive and therapeutic agent for different cancers, including HCC. This study evaluated whether the combination of sorafenib and metformin is sufficient to revert the expression of TIP30, thereby simultaneously reducing lung metastasis and improving survival. Our data show that the combination of sorafenib and metformin inhibits proliferation and invasion in vitro, prolongs median survival, and reduces lung metastasis of HCC in vivo. This effect is closely associated with the upregulation of TIP30, partly through activating AMP-activated protein kinase. Thioredoxin, a prometastasis factor, is negatively regulated by TIP30 and plays an essential role during the process of HCC metastasis. Overall, our results suggest that metformin might be a potent enhancer for the treatment of HCC by using sorafenib.

  1. Downregulation of CD147 expression alters cytoskeleton architecture and inhibits gelatinase production and SAPK pathway in human hepatocellular carcinoma cells

    Directory of Open Access Journals (Sweden)

    Weng Yuan-Yuan

    2008-10-01

    Full Text Available Abstract Background CD147 plays a critical role in the invasive and metastatic activity of hepatocellular carcinoma (HCC cells by stimulating the surrounding fibroblasts to express matrix metalloproteinases (MMPs. Tumor cells adhesion to extracellular matrix (ECM proteins is the first step to the tumor metastasis. MMPs degrade the ECM to promote tumor metastasis. The aim of this study is to investigate the effects of small interfering RNA (siRNA against CD147 (si-CD147 on hepatocellular carcinoma cells' (SMMC-7721 architecture and functions. Methods Flow cytometry and western blot assays were employed to detect the transfection efficiency of si-CD147. Confocal microscopy was used to determine the effects of si-CD147 on SMMC-7721 cells' cytoskeleton. Invasion assay, gelatin zymography and cell adhesion assay were employed to investigate the effects of si-CD147 on SMMC-7721 cells' invasion, gelatinase production and cell adhesive abilities. Western blot assay was utilized to detect the effects of si-CD147 on focal adhesion kinase (FAK, vinculiln and mitogen-activated protein kinase (MAPK expression in SMMC-7721 cells. Results Downregulation of CD147 gene induced the alteration of SMMC-7721 cell cytoskeleton including actin, microtubule and vimentin filaments, and inhibited gelatinase production and expression, cells invasion, FAK and vinculin expression. si-CD147 also blocked SMMC-7721 cells adhesion to collagen IV and phosphorylation level of SAPK/JNKs. SAPK/JNKs inhibitor SP600125 inhibited gelatinase production and expression. Conclusion CD147 is required for normal tumor cell architecture and cell invasion. Downregulation of CD147 affects HCC cell structure and function. Moreover, the alteration of cell behavior may be related to SAPK/JNK Pathway. siRNA against CD147 may be a possible new approach for HCC gene therapy.

  2. Sinulariolide Suppresses Human Hepatocellular Carcinoma Cell Migration and Invasion by Inhibiting Matrix Metalloproteinase-2/-9 through MAPKs and PI3K/Akt Signaling Pathways.

    Science.gov (United States)

    Wu, Yu-Jen; Neoh, Choo-Aun; Tsao, Chia-Yu; Su, Jui-Hsin; Li, Hsing-Hui

    2015-07-20

    Sinulariolide is an active compound isolated from the cultured soft coral Sinularia flexibilis. In this study, we investigate the migration and invasion effects of sinulariolide in hepatocellular carcinoma cell HA22T. Sinulariolide inhibited the migration and invasion effects of hepatocellular carcinoma cells in a concentration-dependent manner. The results of zymography assay showed that sinulariolide suppressed the activities of matrix metalloproteinase (MMP)-2 and MMP-9. Moreover, protein levels of MMP-2, MMP-9, and urokinase-type plasminogen activator (uPA) were reduced by sinulariolide in a concentration-dependent manner. Sinulariolide also exerted an inhibitory effect on phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases (ERK), phosphatidylinositol 3-kinase (PI3K), Akt, Focal adhesion kinase (FAK), growth factor receptor-bound protein 2 (GRB2). Taken together, these results demonstrated that sinulariolide could inhibit hepatocellular carcinoma cell migration and invasion and alter HA22T cell metastasis by reduction of MMP-2, MMP-9, and uPA expression through the suppression of MAPKs, PI3K/Akt, and the FAK/GRB2 signaling pathway. These findings suggest that sinulariolide merits further evaluation as a chemotherapeutic agent for human hepatocellular carcinoma.

  3. ASP5878, a Novel Inhibitor of FGFR1, 2, 3, and 4, Inhibits the Growth of FGF19-Expressing Hepatocellular Carcinoma.

    Science.gov (United States)

    Futami, Takashi; Okada, Hidetsugu; Kihara, Rumi; Kawase, Tatsuya; Nakayama, Ayako; Suzuki, Tomoyuki; Kameda, Minoru; Shindoh, Nobuaki; Terasaka, Tadashi; Hirano, Masaaki; Kuromitsu, Sadao

    2017-01-01

    Hepatocellular carcinoma is an aggressive cancer with poor prognosis. Fibroblast growth factor 19, a member of the fibroblast growth factor family, is a ligand for fibroblast growth factor receptor 4. Moreover, it plays a crucial role in the progression of hepatocellular carcinoma. ASP5878 is a novel inhibitor of fibroblast growth factor receptors 1, 2, 3, and 4 that is under development. It inhibits fibroblast growth factor receptor 4 kinase activity with an IC50 of 3.5 nmol/L. ASP5878 potently suppressed the growth of the fibroblast growth factor 19-expressing hepatocellular carcinoma cell lines Hep3B2.1-7, HuH-7, and JHH-7. In the Hep3B2.1-7 cell line, ASP5878 inhibited the phosphorylation of fibroblast growth factor receptor 4 and its downstream signaling molecules as well as induced apoptosis. Oral administration of ASP5878 at 3 mg/kg induced sustained tumor regression in a subcutaneous xenograft mouse model using Hep3B2.1-7. In HuH-7, an orthotopic xenograft mouse model, ASP5878 induced complete tumor regression and dramatically extended the survival of the mice. These results suggest that ASP5878 is a potentially effective therapeutic agent for hepatocellular carcinoma patients with tumors expressing fibroblast growth factor 19. Mol Cancer Ther; 16(1); 68-75. ©2016 AACR.

  4. Expression of Bcl-2 inhibited Fas-mediated apoptosis in human hepatocellular carcinoma BEL-7404 cells

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Apoptosis plays an important role in embryonic development, tissue remodeling, immune regulation and tumor regression. Two groups of molecules (Bcl-2 family and"Death factor"family) are involved in regulating apoptosis. In order to know about the effect of Bcl-2 on apoptosis induced by Fas, a typical member of"Death factor" family, the transfection experiments with expression vectors pcDNA3-fland pcDNA3-bcl-2 were performed in BEL-7404 cells, a human hepatocellular carcinoma cell line which expresses endogenous Fas, but not FasL and Bcl2. The data showed that the expression of FasL in pcDNA3fl transfected hepatoma cells obviously induced the apoptosis of the cells. However, the overexpression of Bcl-2 in pcDNA3bcl-2 transfected 7404/b-16 cells counteracted pcDNA3-fltransient transfection mediated apoptosis. Further study by cotransfection experiments indicated that Bid but not Bax (both were pro-apoptotic proteins of Bcl-2 family) blocked the inhibitory effect of Bcl-2 on Fas-mediated apoptosis. These results suggested that Fas-mediated apoptosis in human hcpatoma cells is possibly regulated by Bcl-2 family proteins via mitochondria pathway.

  5. Synchronous gastric neuroendocrine carcinoma and hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Ewertsen, Caroline; Henriksen, Birthe Merete; Hansen, Carsten Palnæs

    2009-01-01

    UNLABELLED: Gastric neuroendocrine carcinomas (NECs) are rare tumours that are divided into four subtypes depending on tumour characteristics. Patients with NECs are known to have an increased risk of synchronous and metachronous cancers mainly located in the gastrointestinal tract. A case...... of synchronous gastric NEC and hepatocellular carcinoma in a patient with several other precancerous lesions is presented. The patient had anaemia, and a gastric tumour and two duodenal polyps were identified on upper endoscopy. A CT scan of the abdomen revealed several lesions in the liver. The lesions were...... invisible on B-mode sonography and real-time sonography fused with CT was used to identify and biopsy one of the lesions. Histology showed hepatocellular carcinoma. A literature search showed that only one case of a hepatocellular carcinoma synchronous with a gastric NEC has been reported previously. TRIAL...

  6. Transfer of bcl-xs plasmid is effective in preventing and inhibiting rat hepatocellular carcinoma induced by N-nitrosomorpholine.

    Science.gov (United States)

    Baba, M; Iishi, H; Tatsuta, M

    2001-08-01

    To examine the effect of the bcl-xs gene on the sequence from hepatic precancerous lesions, foci and neoplastic nodules, to hepatocellular carcinomas, Sprague-Dawley rats were given water containing 175 mg/l N-nitrosomorpholine (NNM) for 8 weeks. At weeks 1, 4 and 7, the left lobe of the rat liver was exposed and injected with the bcl-xs plasmid (pCR3.1-rat bcl-xs cDNA) or pCR3.1 encapsulated in cationic empty liposomes each at a dose of 80 microg plasmid/kg body weight. One minute later, low-field-strength, long-duration electric pulses were applied to the left lobe using a pincette electrode with circular poles 1 cm in diameter. The in vivo electroporation procedure significantly increased the transfer of the reporter gene chloramphenicol acetyl transferase (CAT) plasmid via empty liposomes. Thus, CAT mRNA was expressed not only at the sites of electrode contact but at sites 0.5-1.0 cm away from the electrode, and expression also increased with increasing doses of plasmid, meaning that in vivo electroporation enabled the expression of plasmid DNA throughout an extensive area of the rat liver. By week 11, the neoplastic nodules were significantly fewer and smaller in the bcl-xs group than in the pCR3.1 group at the two sites, one with and the other without electrode contact. No hepatocellular carcinomas were found in the rats that had received the bcl-xs plasmid, whereas these tumors were observed in 30% of the rats given pCR3.1. Moreover, overexpression of the bcl-xs protein was detected, and apoptotic activity was significantly increased in the neoplastic nodules, foci and hepatocytes adjacent to the hepatic lesions. These results indicate that the bcl-xs plasmid inhibits the occurrence and growth of rat hepatocellular carcinoma and may thus be effective for the prevention and treatment of human liver tumors.

  7. Hyperthermia inhibits hypoxia-induced epithelial-mesenchymal transition in HepG2 hepatocellular carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    Guang-Jin Yuan; Qian-wen Li; Shun-Lin Shan; Wu-Ming Wang; Sen Jiang; Xi-Ming Xu

    2012-01-01

    AIM:TO investigate the effect of hyperthermia on hypoxia-induced epithelial-mesenchymal transition (EMT)in HepG2 hepatocellular carcinoma (HCC) cells,and its mechanism.METHODS:Cells were treated with hyperthermia at 43 ℃ for 0.5 h,followed by incubation under hypoxic or normoxic conditions for 72 h.Cell morphology was observed.Expressions of E-cadherin and vimentin were determined by immunofluorescence assay or Western blot.The protein and mRNA expressions of Snail were also determined by Western blot and reverse transcription-polymerase chain reaction.Cell migratory capacity was evaluated.RESULTS:Hypoxia induced EMT in HepG2 cells,which was evidenced by morphological,molecular and functional changes,including the formation of a spindle shape and the loss of cell contact.The expression of E-cadherin was decreased but the expression of vimentin was increased; also,the migratory capability was increased by 2.2 ± 0.20-fold as compared with normoxia.However,those effects were inhibited by hyperthermia pretreatment.Furthermore,protein synthesis and mRNA expression of Snail in the cells were enhanced by hypoxia as compared with normoxia,and also significantly inhibited by hyperthermia pretreatment.CONCLUSION:Hyperthermia may inhibit hypoxiainduced EMT in HepG2 HCC cells,and the mechanism may involve inhibition of induced expression of Snail.

  8. Immunology of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Hepatocellular carcinoma (HCC) is primarily a malignancyof the liver, advancing from a damaged, cirrhoticliver to HCC. Globally, HCC is the sixth most prevalentcancer and the third-most prevalent reason for neoplasticdisease-related deaths. A diverse array ofinfiltrating immunocytes regulates the developmentand progression of HCC, as is the case in many othercancers. An understanding of the various immunecomponents during HCC becomes necessary so thatnovel therapeutic strategies can be designed to combatthe disease. A dysregulated immune system (includingchanges in the number and/or function of immunecells, cytokine levels, and the expression of inhibitoryreceptors or their ligands) plays a key role in thedevelopment of HCC. Alterations in either the innateor adaptive arm of the immune system and cross-talkbetween them make the immune system tolerant totumors, leading to disease progression. In this review,we have discussed the status and roles of variousimmune effector cells (e.g. , dendritic cells, natural killercells, macrophages, and T cells), their cytokine profile,and the chemokine-receptor axis in promoting orimpeding HCC.

  9. NDRG2 inhibits hepatocellular carcinoma adhesion, migration and invasion by regulating CD24 expression

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    Tao Yurong

    2011-06-01

    Full Text Available Abstract Background The prognosis of most hepatocellular carcinoma (HCC patients is poor due to the high metastatic rate of the disease. Understanding the molecular mechanisms underlying HCC metastasis is extremely urgent. The role of CD24 and NDRG2 (N-myc downstream-regulated gene 2, a candidate tumor suppressor gene, has not yet been explored in HCC. Methods The mRNA and protein expression of CD24 and NDRG2 was analyzed in MHCC97H, Huh7 and L-02 cells. Changes in cell adhesion, migration and invasion were detected by up- or down-regulating NDRG2 by adenovirus or siRNA. The expression pattern of NDRG2 and CD24 in HCC tissues and the relationship between NDRG2 and HCC clinical features was analyzed by immunohistochemical and western blotting analysis. Results NDRG2 expression was negatively correlated with malignancy in HCC. NDRG2 exerted anti-tumor activity by regulating CD24, a molecule that mediates cell-cell interaction, tumor proliferation and adhesion. NDRG2 up-regulation decreased CD24 expression and cell adhesion, migration and invasion. By contrast, NDRG2 down-regulation enhanced CD24 expression and cell adhesion, migration and invasion. Immunohistochemical analysis of 50 human HCC clinical specimens showed a strong correlation between NDRG2 down-regulation and CD24 overexpression (P = 0.04. In addition, increased frequency of NDRG2 down-regulation was observed in patients with elevated AFP serum level (P = 0.006, late TNM stage (P = 0.009, poor differentiation grade (P = 0.002, tumor invasion (P = 0.004 and recurrence (P = 0.024. Conclusions Our findings indicate that NDRG2 and CD24 regulate HCC adhesion, migration and invasion. The expression level of NDRG2 is closely related to the clinical features of HCC. Thus, NDRG2 plays an important physiological role in HCC metastasis.

  10. Genetic heterogeneity of hepatocellular carcinoma

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    Unsal, H.; Isselbacher, K.J. (Massachusetts General Hospital Cancer Center, Charlestown, MA (United States)); Yakicier, C.; Marcais, C.; Ozturk, M. (Institut National de la Sante et de la Recherche Medicale, Lyon (France)); Kew, M. (Univ. of Witwatersrand, Johannesburg (South Africa)); Volkmann, M. (Univ. of Heidelberg (Germany)); Zentgraf, H. (Deutsches Krebsforschungszentrum, Heidelberg (Germany))

    1994-01-18

    The authors studied 80 hepatocellular carcinomas from three continents for p53 gene (TP53) mutations and hepatitis B virus (HBV) sequences. p53 mutations were frequent in tumors from Mozambique but not in tumors from South Africa, China, and Germany. Independent of geographic origin, most tumors were positive for HBV sequences. X gene coding sequences of HBV were detected in 78% of tumors, whereas viral sequences in the surface antigen- and core antigen-encoding regions were present in less than 35% of tumors. These observations indicate that hepatocellular carcinomas are genetically heterogeneous. Mozambican-types of hepatocellular carcinomas are characterized by a high incidence of p53 mutations related to aflatoxins. In other tumors, the rarity of p53 mutations combined with the frequent presence of viral X gene coding sequences suggests a possible interference of HBV with the wild-type p53 function.

  11. Damnacanthal, a noni anthraquinone, inhibits c-Met and is a potent antitumor compound against Hep G2 human hepatocellular carcinoma cells.

    Science.gov (United States)

    García-Vilas, Javier A; Quesada, Ana R; Medina, Miguel A

    2015-01-26

    Damnacanthal, an anthraquinone present in noni plants, targets several tyrosine kinases and has antitumoral effects. This study aims at getting additional insight on the potential of damnacanthal as a natural antitumor compound. The direct effect of damnacanthal on c-Met was tested by in vitro activity assays. Additionally, Western blots of c-Met phosphorylation in human hepatocellular carcinoma Hep G2 cells were performed. The antitumor effects of damnacanthal were tested by using cell growth, soft agar clonogenic, migration and invasion assays. Their mechanisms were studied by Western blot, and cell cycle, apoptosis and zymographic assays. Results show that damnacanthal targets c-Met both in vitro and in cell culture. On the other hand, damnacanthal also decreases the phosphorylation levels of Akt and targets matrix metalloproteinase-2 secretion in Hep G2 cells. These molecular effects are accompanied by inhibition of the growth and clonogenic potential of Hep G2 hepatocellular carcinoma cells, as well as induction of Hep G2 apoptosis. Since c-Met has been identified as a new potential therapeutical target for personalized treatment of hepatocellular carcinoma, damnacanthal and noni extract supplements containing it could be potentially interesting for the treatment and/or chemoprevention of hepatocellular carcinoma through its inhibitory effects on the HGF/c-Met axis.

  12. Matrine derivative WM130 inhibits hepatocellular carcinoma by suppressing EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways.

    Science.gov (United States)

    Qian, Liqiang; Liu, Yan; Xu, Yang; Ji, Weidan; Wu, Qiuye; Liu, Yongjing; Gao, Quangen; Su, Changqing

    2015-11-01

    Matrine, a sophora alkaloid, has been demonstrated to exert antitumor effects on many types of cancer. However, its bioactivity is weak and its potential druggability is low. We modified the structure of matrine and obtained a new matrine derivative, WM130 (C30N4H40SO5F), which exhibited better pharmacological activities than matrine. In this study, we investigated the antitumor activity and the underlying mechanisms of WM130 on hepatocellular carcinoma (HCC) cells in vitro and in vivo, and found that WM130 inhibited the proliferation, invasion, migration and induced apoptosis of HCC cells in a dose-dependent manner. Furthermore, after treatment with WM130, the expressions of p-EGFR, p-ERK, p-AKT, MMP-2 and the ratio of Bcl-2/Bax were significantly down-regulated, whereas the expression of PTEN was increased in HCC cells. Moreover, WM130 inhibited Huh-7 xenograft tumor growth in a dose-dependent manner after intravenous administration. Immunohistochemistry results demonstrated that WM130 treatment resulted in down-regulation of p-EGFR, MMP-2, and Ki67 and up-regulation of PTEN. The findings indicated that WM130 could inhibit cell proliferation, invasion, migration and induced apoptosis in HCC cells by suppressing EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways and may be a novel effective candidate for HCC treatment.

  13. Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma

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    Zhou, Qian; Wong, Chi Hang; Lau, Cecilia Pik Yuk; Hui, Connie Wun Chun; Lui, Vivian Wai Yan; Chan, Stephen Lam; Yeo, Winnie

    2013-01-01

    Mammalian target of rapamycin (mTOR) and the microtubules are shown to be potential targets for treating hepatocellular carcinoma (HCC). PI3K/Akt/mTOR activation is associated with resistance to microtubule inhibitors. Here, we evaluated the antitumor activity by cotargeting of the mTOR (using allosteric mTOR inhibitor everolimus) and the microtubules (using novel microtubule-stabilizing agent patupilone) in HCC models. In vitro studies showed that either targeting mTOR signaling with everolimus or targeting microtubules with patupilone was able to suppress HCC cell growth in a dose-dependent manner. Cotargeting of the mTOR (by everolimus) and the microtubules (by patupilone, at low nM) resulted in enhanced growth inhibition in HCC cells (achieving maximal growth inhibition of 60–87%), demonstrating potent antitumor activity of this combination. In vivo studies showed that everolimus treatment alone for two weeks was able to inhibit the growth of Hep3B xenografts. Strikingly, the everolimus/patupilone combination induced a more significant antitumor activity. Mechanistic study demonstrated that this enhanced antitumor effect was accompanied by marked cell apoptosis induction and antiangiogenic activity, which were more significant than single-agent treatments. Our findings demonstrated that the everolimus/patupilone combination, which had potent antitumor activity, was a potential therapeutic strategy for HCC. PMID:23509629

  14. Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma

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    Qian Zhou

    2013-01-01

    Full Text Available Mammalian target of rapamycin (mTOR and the microtubules are shown to be potential targets for treating hepatocellular carcinoma (HCC. PI3K/Akt/mTOR activation is associated with resistance to microtubule inhibitors. Here, we evaluated the antitumor activity by cotargeting of the mTOR (using allosteric mTOR inhibitor everolimus and the microtubules (using novel microtubule-stabilizing agent patupilone in HCC models. In vitro studies showed that either targeting mTOR signaling with everolimus or targeting microtubules with patupilone was able to suppress HCC cell growth in a dose-dependent manner. Cotargeting of the mTOR (by everolimus and the microtubules (by patupilone, at low nM resulted in enhanced growth inhibition in HCC cells (achieving maximal growth inhibition of 60–87%, demonstrating potent antitumor activity of this combination. In vivo studies showed that everolimus treatment alone for two weeks was able to inhibit the growth of Hep3B xenografts. Strikingly, the everolimus/patupilone combination induced a more significant antitumor activity. Mechanistic study demonstrated that this enhanced antitumor effect was accompanied by marked cell apoptosis induction and antiangiogenic activity, which were more significant than single-agent treatments. Our findings demonstrated that the everolimus/patupilone combination, which had potent antitumor activity, was a potential therapeutic strategy for HCC.

  15. Tanshinone IIA inhibits metastasis after palliative resection of hepatocellular carcinoma and prolongs survival in part via vascular normalization

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    Wang Wen-Quan

    2012-11-01

    Full Text Available Abstract Background Promotion of endothelial normalization restores tumor oxygenation and obstructs tumor cells invasion, intravasation, and metastasis. We therefore investigated whether a vasoactive drug, tanshinone IIA, could inhibit metastasis by inducing vascular normalization after palliative resection (PR of hepatocellular carcinoma (HCC. Methods A liver orthotopic double-tumor xenograft model in nude mouse was established by implantation of HCCLM3 (high metastatic potential and HepG2 tumor cells. After removal of one tumor by PR, the effects of tanshinone IIA administration on metastasis, tumor vascularization, and survival were evaluated. Tube formation was examined in mouse tumor-derived endothelial cells (TECs treated with tanshinone IIA. Results PR significantly accelerated residual hepatoma metastases. Tanshinone IIA did not inhibit growth of single-xenotransplanted tumors, but it did reduce the occurrence of metastases. Moreover, it inhibited PR-enhanced metastases and, more importantly, prolonged host survival. Tanshinone IIA alleviated residual tumor hypoxia and suppressed epithelial-mesenchymal transition (EMT in vivo; however, it did not downregulate hypoxia-inducible factor 1α (HIF-1α or reverse EMT of tumor cells under hypoxic conditions in vitro. Tanshinone IIA directly strengthened tube formation of TECs, associated with vascular endothelial cell growth factor receptor 1/platelet derived growth factor receptor (VEGFR1/PDGFR upregulation. Although the microvessel density (MVD of residual tumor tissue increased after PR, the microvessel integrity (MVI was still low. While tanshinone IIA did not inhibit MVD, it did dramatically increase MVI, leading to vascular normalization. Conclusions Our results demonstrate that tanshinone IIA can inhibit the enhanced HCC metastasis associated with PR. Inhibition results from promoting VEGFR1/PDGFR-related vascular normalization. This application demonstrates the potential clinical

  16. Tumor progression locus 2 ablation suppressed hepatocellular carcinoma development by inhibiting hepatic inflammation and steatosis in mice

    Science.gov (United States)

    Background: Tumor progression locus 2 (TPL2), a serine threonine kinase, functions as a critical regulator of inflammatory pathways and mediates oncogenic events. The potential role of Tpl2 in nonalcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC) development remains unkn...

  17. Klf4 inhibits tumor growth and metastasis by targeting microRNA-31 in human hepatocellular carcinoma

    Science.gov (United States)

    Tian, Chuan; Yao, Shanshan; Liu, Li; Ding, Youcheng; Ye, Qingwang; Dong, Xiao; Gao, Yong; Yang, Ning; Li, Qi

    2017-01-01

    MicroRNAs (miRNAs or miRs) are short, endogenous non-coding RNA molecules, demonstrating abnormal expression in cancer initiation and progression. In this study, we profiled 18 differentially regulated miRNAs, including miRNA-31, using miRNA array. Kruppel (or Krüppel)-like factor 4 (Klf4) is a transcription factor and putative tumor suppressor. Both were found to be significantly downregulated in liver cancer tissues and cells. However, little is known about the correlation between Klf4 and miRNA-31 in hepatocellular carcinoma (HCC). The mRNA expression of Klf4 was decreased and inversely associated with the clinical stage, T classification and hepatitis B in patients with HCC, while the expression of miR-31 was lower (r=0.326, P=0.018). Using cell counting kit 8 (CCK8) and Transwell migration assays, we found that Klf4 and miR-31 inhibited the proliferation and metastasis of liver cancer cells. Moreover, we demonstrated that Klf4 directly binds to the promoter of miR-31 and activates its transcription. In vitro experiments confirmed that Klf4 regulated miR-31 and thereby inhibited HCC cell growth and metastasis. Taken together, our findings indicate that Klf4 directly regulates miR-31 in HCC. Thus, miR-31 may serve as a potential diagnostic marker and therapeutic target in HCC. PMID:27909734

  18. Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models.

    Science.gov (United States)

    Desnoyers, L R; Pai, R; Ferrando, R E; Hötzel, K; Le, T; Ross, J; Carano, R; D'Souza, A; Qing, J; Mohtashemi, I; Ashkenazi, A; French, D M

    2008-01-03

    Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice its involvement in human cancer is not well characterized. Here we report that FGF19 and its cognate receptor FGF receptor 4 (FGFR4) are coexpressed in primary human liver, lung and colon tumors and in a subset of human colon cancer cell lines. To test the importance of FGF19 for tumor growth, we developed an anti-FGF19 monoclonal antibody that selectively blocks the interaction of FGF19 with FGFR4. This antibody abolished FGF19-mediated activity in vitro and inhibited growth of colon tumor xenografts in vivo and effectively prevented hepatocellular carcinomas in FGF19 transgenic mice. The efficacy of the antibody in these models was linked to inhibition of FGF19-dependent activation of FGFR4, FRS2, ERK and beta-catenin. These findings suggest that the inactivation of FGF19 could be beneficial for the treatment of colon cancer, liver cancer and other malignancies involving interaction of FGF19 and FGFR4.

  19. MicroRNA-186 targets Yes-associated protein 1 to inhibit Hippo signaling and tumorigenesis in hepatocellular carcinoma.

    Science.gov (United States)

    Ruan, Tingyan; He, Xiaoting; Yu, Jun; Hang, Zhiqiang

    2016-04-01

    Liver cancer, particularly hepatocellular carcinoma (HCC), is one of leading causes of cancer-related mortality worldwide. Upregulation of the evolutionary conserved Hippo signaling pathway has been observed in HCC patients, and Yes-associated protein 1 (YAP1) has been reported to play a key role in HCC tumorigenesis. microRNAs (miRNAs) are a family of small non-coding RNAs, usually 21-25 nucleotides in length, and are essential in the regulation of gene expression. Abnormal miRNA expression has been implicated in the initiation and progression of numerous forms of cancers, including liver cancer. Here, we report the identification of a novel miRNA, miR-186, and its functions as an HCC tumor suppressor. We observed that miR-186 was downregulated in several HCC cell lines, and that it directly targets YAP1 mRNA. Overexpression of miR-186 in HCC cells significantly downregulates YAP1 mRNA and protein levels, leading to downregulation of the Hippo signaling pathway, which in turn severely inhibits HCC cell migration, invasion and proliferation. Our study is the first to report the direct involvement of miR-186 in downregulating YAP1 and, more significantly, inhibiting HCC tumorigenesis, and supports the role miR-186 as a potential therapeutic target in treating liver cancer.

  20. New Insights in Hepatocellular Carcinoma

    NARCIS (Netherlands)

    C.D.M. Witjes (Carlijn)

    2012-01-01

    textabstractHepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer mortality. HCC is one of the few cancers with well-defined major risk factors. Worldwide, in 80% of the cases HCC develops in cirrhotic livers, and cirrhosis is the stronges

  1. Antrodia cinnamomea Inhibits Migration in Human Hepatocellular Carcinoma Cells: The Role of ERp57 and PGK-1.

    Science.gov (United States)

    Chen, Ying-Yi; Liu, Fon-Chang; Wu, Tian-Shung; Sheu, Ming-Jyh

    2015-01-01

    Evidences suggest that ERp57 and PGK-1 signaling lead to cancer cell proliferation and migration. We hypothesized that ERp57 and PGK-1 down-regulation may inactivate matrix metalloproteinase (MMP)-2, -9 expressions and inhibit hepatocellular carcinoma (HCC) migration. Antrodia cinnamomea is widely prescribed as an adjuvant to treat HCC in Taiwan. We aimed to investigate if ethanol extract of fruiting bodies of Antrodia cinnamomea (EEAC) and its active ingredients (i.e., zhankuic acid A, cordycepin, and adenosine) can modulate HCC cancer cells migration through ERp57 and PGK-1 and other molecular pathways such as PI3K/Akt and MAPK. ERp57 and PGK-1 siRNA were transfected into HCC to determine effects on MMP-2/-9 expressions and cell migration. We then examined the inhibitory effects of EEAC and its active ingredients on HCC migration and its related mechanisms including ERp57, PGK-1, PI3K/Akt, and MAPK signaling pathways. Down-regulation of ERp57 and PGK-1 by siRNA decreased MMP-2, -9 expressions and Transwell cell migration in HCC. Nontoxic EEAC markedly inhibited migration of HCC, and significantly inhibited activities and protein expressions of MMP-2 and -9, while the expression of the endogenous inhibitors (TIMP-1 and TIMP-2) of these proteins increased. Nontoxic EEAC and its active ingredients decreased ERp57, GLUD-1, GST-pi, and PGK-1 protein expressions. Finally, nontoxic EEAC inhibited the phosphorylated FAK, PI3K/Akt, and MAPK signaling. Our findings first indicate that EEAC and its ingredients effectively suppress HCC migration. Additionally, the molecular mechanisms appear to be mediated, in part, through the down-regulation of ERp57, PGK-1, MAPK, and PI3K/Akt.

  2. The silencing of Pokemon attenuates the proliferation of hepatocellular carcinoma cells in vitro and in vivo by inhibiting the PI3K/Akt pathway.

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    Chan-Chan Lin

    Full Text Available Pokemon (POK erythroid myeloid ontogenic factor, which belongs to the POK protein family, is also called LRF, OCZF and FBI-1. As a transcriptional repressor, Pokemon assumes a critical function in cellular differentiation and oncogenesis. Our study identified an oncogenic role for Pokemon in human hepatocellular carcinoma (HCC. We successfully established human HepG2 and Huh-7 cell lines in which Pokemon was stably knocked down. We demonstrated that Pokemon silencing inhibited cell proliferation and migration. Pokemon knockdown inhibited the PI3K/Akt and c-Raf/MEK/ERK pathways and modulated the expression of various cell cycle regulators in HepG2 and Huh-7 cells. Therefore, Pokemon may also be involved in cell cycle progression in these cells. We confirmed that Pokemon silencing suppresses hepatocellular carcinoma growth in tumor xenograft mice. These results suggest that Pokemon promotes cell proliferation and migration in hepatocellular carcinoma and accelerates tumor development in an Akt- and ERK-signaling-dependent manner.

  3. Anti-tumor effect of 5-aza-2'-deoxycytidine by inhibiting telomerase activity in hepatocellular carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    Shuang-Fen Tao; Chang-Song Zhang; Xian-Ling Guo; Yun Xu; Shan-Shan Zhang; Jian-Rui Song; Rong Li

    2012-01-01

    AIM:To investigate the effect of the demethylating reagent 5-aza-2'-deoxycitidine (DAC) on telomerase activity in hepatocellular carcinoma (HCC) cell lines,SMMC-7721 and HepG2.METHODS:The related gene expression in cell lines was examined by real-time reverse transcription-polymerase chain reaction and Western blotting analysis.The telomerase activity was examined by telomeric repeat amplification protocol-enzyme-linked immunosorbent assay and DNA methylation was determined by methylation-specific polymerase chain reaction.RESULTS:The telomerase activity was significantly reduced in both cell lines treated with DAC,accompanied by downregulation of telomerase reverse transcriptase (hTERT).We also observed the effect of DAC on the methylation status of hTERT promoter and the expression of regulatory genes,such as c-myc,p15,p16,p21,E2F1,and WT1.The methylation status of hTERT promoter could be reversed in SMMC-7721 by DAC,but not in HepG2 cells.However,p16 expression could be reactivated by demethylation of its promoter,and c-Myc expression was repressed in both cell lines.Moreover,DAC could enhance the sensitivity to the chemotherapeutic agents,such as cisplatin,by induction of apoptosis of HCC cells.CONCLUSION:The DAC exerts its anti-tumor effects in HCC cells by inhibiting the telomerase activity.

  4. Systemic delivery of microRNA-101 potently inhibits hepatocellular carcinoma in vivo by repressing multiple targets.

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    Fang Zheng

    2015-02-01

    Full Text Available Targeted therapy based on adjustment of microRNA (miRNAs activity takes great promise due to the ability of these small RNAs to modulate cellular behavior. However, the efficacy of miR-101 replacement therapy to hepatocellular carcinoma (HCC remains unclear. In the current study, we first observed that plasma levels of miR-101 were significantly lower in distant metastatic HCC patients than in HCCs without distant metastasis, and down-regulation of plasma miR-101 predicted a worse disease-free survival (DFS, P<0.05. In an animal model of HCC, we demonstrated that systemic delivery of lentivirus-mediated miR-101 abrogated HCC growth in the liver, intrahepatic metastasis and distant metastasis to the lung and to the mediastinum, resulting in a dramatic suppression of HCC development and metastasis in mice without toxicity and extending life expectancy. Furthermore, enforced overexpression of miR-101 in HCC cells not only decreased EZH2, COX2 and STMN1, but also directly down-regulated a novel target ROCK2, inhibited Rho/Rac GTPase activation, and blocked HCC cells epithelial-mesenchymal transition (EMT and angiogenesis, inducing a strong abrogation of HCC tumorigenesis and aggressiveness both in vitro and in vivo. These results provide proof-of-concept support for systemic delivery of lentivirus-mediated miR-101 as a powerful anti-HCC therapeutic modality by repressing multiple molecular targets.

  5. Fisetin Modulates Antioxidant Enzymes and Inflammatory Factors to Inhibit Aflatoxin-B1 Induced Hepatocellular Carcinoma in Rats.

    Science.gov (United States)

    Maurya, Brajesh Kumar; Trigun, Surendra Kumar

    2016-01-01

    Fisetin, a known antioxidant, has been found to be cytotoxic against certain cell lines. However, the mechanism by which it inhibits tumor growth in vivo remains unexplored. Recently, we have demonstrated that Aflatoxin-B1 (AFB1) induced hepatocarcinogenesis is associated with activation of oxidative stress-inflammatory pathway in rat liver. The present paper describes the effect of in vivo treatment with 20 mg/kg b.w. Fisetin on antioxidant enzymes vis-a-vis oxidative stress level and on the profile of certain proinflammatory cytokines in the hepatocellular carcinoma (HCC) induced by two doses of 1 mg/kg b.w. AFB1 i.p. in rats. The reduced levels of most of the antioxidant enzymes, coinciding with the enhanced level of reactive oxygen species in the HCC liver, were observed to regain their normal profiles due to Fisetin treatment. Also, Fisetin treatment could normalize the enhanced expression of TNFα and IL1α, the two proinflammatory cytokines, reported to be involved in HCC pathogenesis. These observations were consistent with the regression of neoplastic lesion and declined GST-pi (placental type glutathione-S-transferase) level, a HCC marker, in the liver of the Fisetin treated HCC rats. The findings suggest that Fisetin attenuates oxidative stress-inflammatory pathway of AFB1 induced hepatocarcinogenesis.

  6. Fisetin Modulates Antioxidant Enzymes and Inflammatory Factors to Inhibit Aflatoxin-B1 Induced Hepatocellular Carcinoma in Rats

    Directory of Open Access Journals (Sweden)

    Brajesh Kumar Maurya

    2016-01-01

    Full Text Available Fisetin, a known antioxidant, has been found to be cytotoxic against certain cell lines. However, the mechanism by which it inhibits tumor growth in vivo remains unexplored. Recently, we have demonstrated that Aflatoxin-B1 (AFB1 induced hepatocarcinogenesis is associated with activation of oxidative stress-inflammatory pathway in rat liver. The present paper describes the effect of in vivo treatment with 20 mg/kg b.w. Fisetin on antioxidant enzymes vis-a-vis oxidative stress level and on the profile of certain proinflammatory cytokines in the hepatocellular carcinoma (HCC induced by two doses of 1 mg/kg b.w. AFB1 i.p. in rats. The reduced levels of most of the antioxidant enzymes, coinciding with the enhanced level of reactive oxygen species in the HCC liver, were observed to regain their normal profiles due to Fisetin treatment. Also, Fisetin treatment could normalize the enhanced expression of TNFα and IL1α, the two proinflammatory cytokines, reported to be involved in HCC pathogenesis. These observations were consistent with the regression of neoplastic lesion and declined GST-pi (placental type glutathione-S-transferase level, a HCC marker, in the liver of the Fisetin treated HCC rats. The findings suggest that Fisetin attenuates oxidative stress-inflammatory pathway of AFB1 induced hepatocarcinogenesis.

  7. miR-592/WSB1/HIF-1α axis inhibits glycolytic metabolism to decrease hepatocellular carcinoma growth

    Science.gov (United States)

    Song, Ying; Liu, Mei-You; Yang, Xiao-Juan; Xue, Yan; Wen, Ai-Dong; Shi, Lei

    2016-01-01

    Hepatocellular carcinoma (HCC) cells rapidly switch their energy source from oxidative phosphorylation to glycolytic metabolism in order to efficiently proliferate. However, the molecular mechanisms responsible for this switch remain unclear. In this study, we found that miR-592 was frequently downregulated in human HCC tissues and cell lines, and its downregulation was closely correlated with aggressive clinicopathological features and poor prognosis of HCC patients. Overexpression of miR-592 inhibited aerobic glycolysis and proliferation in HCC cells in vitro. Conversely, knockdown of miR-592 promoted HCC growth in both subcutaneous injection and orthotopic liver tumor implantation models in vivo. Mechanistically, miR-592 downregulation in human HCCs was correlated with an upregulation of WD repeat and SOCS box containing 1 (WSB1). We further showed that miR-592 directly binds to the 3′-UTR of the WSB1 gene, thus disrupting hypoxia inducible factor-1α (HIF-1α) protein stabilization. In turn, overexpression of WSB1 in HCC cells rescued decreased HIF-1α expression, glucose uptake, and HCC growth induced by miR-592. Collectively, our clinical data and functional studies suggest that miR-592 is a new robust inhibitor of the Warburg effect and a promising therapeutic target for HCC treatment. PMID:27153552

  8. Pioglitazone, a PPARγ agonist, inhibits growth and invasion of human hepatocellular carcinoma via blockade of the rage signaling.

    Science.gov (United States)

    Yang, Yuan; Zhao, Ling-Hao; Huang, Bo; Wang, Ruo-Yu; Yuan, Sheng-Xian; Tao, Qi-Fei; Xu, Yong; Sun, Han-Yong; Lin, Chuan; Zhou, Wei-Ping

    2015-12-01

    Pioglitazone (PGZ), a synthetic PPARγ ligand, is known to have anti-tumor activity. However, it is unclear how it acts against hepatocellular carcinoma (HCC). We hypothesized that the pathological receptor for advanced glycation end products (RAGE) is involved in the PGZ anti-tumor process. To test this notion, human primary HCC tissues and corresponding adjacent non-cancerous tissues (ANCT) from 75 consecutive cases were analyzed. The expression and clinical significance of RAGE was assessed by immunohistochemical assay through tissue microarray. After HCC cells were pretreated with different concentrations of PGZ, cell proliferation, apoptosis, cell invasion, and cell cycle distribution were evaluated by multiple assays. The results showed that, the positive expression of RAGE was significantly higher in HCC tissues than in ANCT (66.7% vs. 36.0%, P RAGE, NF-κB, HMGB1, p38MAPK, Ki-67, MMP-2, and CyclinD1. Furthermore, knockdown of RAGE or NF-κB by siRNA effectively suppressed cell proliferation and invasion, and mediated the inhibitory effects of PGZ in HCC cells. Taken together, our findings suggest that, RAGE is overexpressed in human HCC tissues, and is closely associated with the pathological staging and tumor invasion of HCC. In addition, PGZ as a PPARγ agonist may inhibit growth and invasion of HCC cells via blockade of the RAGE signaling. © 2014 Wiley Periodicals, Inc.

  9. Isocorydine inhibits cell proliferation in hepatocellular carcinoma cell lines by inducing G2/m cell cycle arrest and apoptosis.

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    Hefen Sun

    Full Text Available The treatment of human hepatocellular carcinoma (HCC cell lines with (+-isocorydine, which was isolated and purified from Papaveraceae sp. plants, resulted in a growth inhibitory effect caused by the induction of G2/M phase cell cycle arrest and apoptosis. We report that isocorydine induces G2/M phase arrest by increasing cyclin B1 and p-CDK1 expression levels, which was caused by decreasing the expression and inhibiting the activation of Cdc25C. The phosphorylation levels of Chk1 and Chk2 were increased after ICD treatment. Furthermore, G2/M arrest induced by ICD can be disrupted by Chk1 siRNA but not by Chk2 siRNA. In addition, isocorydine treatment led to a decrease in the percentage of CD133(+ PLC/PRF/5 cells. Interestingly, isocorydine treatment dramatically decreased the tumorigenicity of SMMC-7721 and Huh7 cells. These findings indicate that isocorydine might be a potential therapeutic drug for the chemotherapeutic treatment of HCC.

  10. Pim-2 activates API-5 to inhibit the apoptosis of hepatocellular carcinoma cells through NF-kappaB pathway.

    Science.gov (United States)

    Ren, Ke; Zhang, Wei; Shi, Yujun; Gong, Jianping

    2010-06-01

    Pim-2 is proved to be relevant to the tumorigenesis of hepatocellular carcinoma (HCC), but the mechanism is unclear. We studied the relationship among Pim-2, NF-kappaB and API-5. In our experiment, expression level of the three factors and phosphorylation level of API-5, as well as NF-kappaB activity, were detected in HCC tissues and the nontumorous controls. Then Pim-2 gene was transfected into nontumorous liver cells L02, and Pim-2 SiRNA was transfected into hepatoblastoma cell line HepG2. Parthenolide was added as NF-kappaB inhibitor. The same detections as above were repeated in the cells, along with the apoptosis analysis. We found the levels of Pim-2, NF-kappaB and API-5, as well as NF-kappaB activity, were significantly higher in HCC tissues. Pim-2 level was increased in L02 cells after the transfection of Pim-2 gene, but decreased in HepG2 cells after the transfection of Pim-2 SiRNA. The levels of NF-kappaB and API-5, as well as NF-kappaB activity and API-5 phosphorylation level, were in accordance with Pim-2 level, but could be reversed by Parthenolide. Cell apoptosis rates were negatively correlated with API-5 phosphorylation level. Therefore, we infer that Pim-2 could activate API-5 to inhibit the apoptosis of liver cells, and NF-kappaB is the key regulator.

  11. Inhibitory effects of xanthohumol from hops (Humulus lupulus L.) on human hepatocellular carcinoma cell lines.

    Science.gov (United States)

    Ho, Yi-Chien; Liu, Chi-Hsien; Chen, Chien-Nan; Duan, Kow-Jen; Lin, Ming-Tse

    2008-11-01

    Xanthohumol is one of the main flavonoids in hop extracts and in beer. Very few investigations of xanthohumol have studied hepatocellular carcinoma. In this study, the inhibitory effects of xanthohumol on human hepatocellular carcinoma cell lines were investigated. The IC(50) values of xanthohumol for two hepatocellular carcinoma cell lines and one normal hepatocyte cell line were 108, 166 and 211 microm, respectively. Normal murine hepatocyte cell line had more resistance to xanthohumol than hepatocellular carcinoma cell lines. Besides, the inhibitory effects of xanthohumol on human hepatocellular carcinoma cell lines were attributed to apoptosis as indicated in the results of flow cytometry, fluorescent nuclear staining and electrophoresis of oligonucleosomal DNA fragments. Hop xanthohumol was more efficient in the growth inhibition of hepatocellular carcinoma cell lines than the flavonoids silibinin and naringin from thistle and citrus. It was shown for the first time that xanthohumol from hops effectively inhibits proliferation of human hepatocellular carcinoma cells in vitro.

  12. MEK-ERK inhibition potentiates WAY-600-induced anti-cancer efficiency in preclinical hepatocellular carcinoma (HCC) models

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Kaifeng, E-mail: kaifeng_wangdr@sina.com [Cancer center, the Affiliated Hospital of Hangzhou Normal University, Hangzhou (China); Fan, Yaohua [Oncology Department, No. 1 Hospital of Jiaxing, Zhejiang Province, Jiaxing (China); Chen, Gongying [Oncology Department, The Affiliated Hospital Hangzhou Normal University, Hangzhou (China); Wang, Zhengrong [Taizhou Hospital, Zhejiang Province, Taizhou (China); Kong, Dexin; Zhang, Peng [Oncology Department, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou (China)

    2016-05-27

    The search for novel anti-hepatocellular carcinoma (HCC) agents is important. Mammalian target of rapamycin (mTOR) hyper-activation plays a pivotal role in promoting HCC tumorigenesis and chemoresistance. The current preclinical study evaluated the potential anti-HCC activity by a potent mTOR kinase inhibitor, WAY-600. We showed that WAY-600 inhibited survival and proliferation of HCC cell lines (HepG2 and Huh7) and primary human HCC cells. Caspase-dependent apoptosis was activated by WAY-600 in above HCC cells. Reversely, caspase inhibitors largely attenuated WAY-600's lethality against HCC cells. At the signaling level, WAY-600 blocked mTOR complex 1/2 (mTORC1/2) assemble and activation, yet activated MEK-ERK pathway in HCC cells. MEK-ERK inhibitors, PD-98059 and MEK-162, or MEK1/2 shRNA significantly potentiated WAY-600's cytotoxicity in HCC cells. Further studies showed that WAY-600 intraperitoneal (i.p.) administration in nude mice inhibited p-AKT Ser-473 and displayed significant anti-cancer activity against HepG2 xenografts. Remarkably, co-administration of MEK-162 further potentiated WAY-600's anti-HCC activity in vivo. These preclinical results demonstrate the potent anti-HCC activity by WAY-600, either alone or with MEK-ERK inhibitors. -- Highlights: •WAY-600 inhibits HCC cell survival and proliferation in vitro. •WAY-600 activates caspase-dependent apoptosis in HCC cells. •WAY-600 blocks mTORC1/2 activation, but activates MEK-ERK in HCC cells. •MEK-ERK inhibitors or MEK1/2 shRNA enhances WAY-600's cytotoxicity against HCC cells. •MEK-162 co-administration potentiates WAY-600-induced the anti-HepG2 tumor efficacy.

  13. Telomerase inhibition decreases alpha-fetoprotein expression and secretion by hepatocellular carcinoma cell lines: in vitro and in vivo study.

    Directory of Open Access Journals (Sweden)

    Roula Tahtouh

    Full Text Available Alpha-fetoprotein (AFP is a diagnostic marker for hepatocellular carcinoma (HCC. A direct relationship between poor prognosis and the concentration of serum AFP has been observed. Telomerase, an enzyme that stabilizes the telomere length, is expressed by 90% of HCC. The aim of this study was to investigate the effect of telomerase inhibition on AFP secretion and the involvement of the PI3K/Akt/mTOR signaling pathway. Proliferation and viability tests were performed using tetrazolium salt. Apoptosis was determined through the Annexin V assay using flow cytometry. The concentrations of AFP were measured using ELISA kits. The AFP mRNA expression was evaluated using RT-PCR, and cell migration was evaluated using a Boyden chamber assay. The in vivo effect of costunolide on AFP production was tested in NSG mice. Telomerase inhibition by costunolide and BIBR 1532 at 5 and 10 μM decreased AFP mRNA expression and protein secretion by HepG2/C3A cells. The same pattern was obtained with cells treated with hTERT siRNA. This treatment exhibited no apoptotic effect. The AFP mRNA expression and protein secretion by PLC/PRF/5 was decreased after treatment with BIBR1532 at 10 μM. In contrast, no effect was obtained for PLC/PRF/5 cells treated with costunolide at 5 or 10 μM. Inhibition of the PI3K/Akt/mTOR signaling pathway decreased the AFP concentration. In contrast, the MAPK/ERK pathway appeared to not be involved in HepG2/C3A cells, whereas ERK inhibition decreased the AFP concentration in PLC/PRF/5 cells. Modulation of the AFP concentration was also obtained after the inhibition or activation of PKC. Costunolide (30 mg/kg significantly decreased the AFP serum concentration of NSG mice bearing HepG2/C3A cells. Both the inhibition of telomerase and the inhibition of the PI3K/Akt/mTOR signaling pathway decreased the AFP production of HepG2/C3A and PLC/PRF/5 cells, suggesting a relationship between telomerase and AFP expression through the PI3K

  14. Proteomics in Discovery of Hepatocellular Carcinoma Biomarkers

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective: To discover new proteomic biomarkers of hepatocellular carcinoma. Methods: Surface enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry was used to discover biomarkers for differentiating hepatocellular carcinoma and chronic liver disease. A population of 50 patients with hepatocellular carcinoma and 33 patients with chronic liver disease was studied. Results: Twelve proteomic biomarkers of hepatocellular carcinoma were detected in this study. Three proteomic biomarkers were highly expressed in hepatocellular carcinoma and nine proteomic biomarkers were highly expressed in chronic liver disease. The most valuable proteomic biomarker with m/z=11498 had no similar diagnostic value as α-fetoprotein. Conclusion:Some of the twelve proteomic biomarkers may become new biomarkers of hepatocellular carcinoma.

  15. Berberine suppresses Id-1 expression and inhibits the growth and development of lung metastases in hepatocellular carcinoma.

    Science.gov (United States)

    Tsang, Chi Man; Cheung, Kenneth Chat Pan; Cheung, Yuk Chun; Man, Kwan; Lui, Vivian Wai-Yan; Tsao, Sai Wah; Feng, Yibin

    2015-03-01

    Hepatocellular carcinoma (HCC) is an invasive cancer with a high rate of recurrence and metastasis. Agents with anti-proliferative as well as anti-metastatic activity will be ideal for effective treatment. Here, we demonstrated that berberine, an isoquinoline alkaloid, harbored potent anti-metastatic and anti-proliferative activities in vivo. Using an orthotopic model of HCC (MHCC-97L), which spontaneously develops lung metastases (one of the most common sites of HCC metastasis), we found that berberine treatment (10mg/kg/2days) significantly reduced lung metastasis from the liver tumors by ~85% (quantitated by bioluminescence emitted from lung metastases). Histological examination also confirmed the reduced incidence and number of lung metastases in berberine-treated mice. Furthermore, berberine effectively suppressed extra-tumor invasion of the primary HCC implant into the surrounding normal liver tissue, illustrating its potent anti-metastatic action in vivo. Consistent with previous reports in other cancer, berberine's anti-tumor activity was accompanied by suppression of cellular proliferation, invasiveness and HIF-1α/VEGF signaling. Strikingly, further mechanistic investigation revealed that berberine exerted profound inhibitory effect on the expression of Id-1, which is a key regulator for HCC development and metastasis. Berberine could suppress the transcription level of Id-1 through inhibiting its promotor activity. Specific downregulation of Id-1 by knocking down its RNA transcripts in HCC cells inhibited cellular growth, invasion and VEGF secretion, demonstrating the functional relevance of Id-1 downregulation induced by berberine. Lastly, berberine's anti-proliferative and anti-invasive activities could be partially rescued by Id-1 overexpression in HCC models, revealing a novel anti-cancer/anti-invasive mechanism of berberine via Id-1 suppression.

  16. Quercetin-3-O-glucoside induces human DNA topoisomerase II inhibition, cell cycle arrest and apoptosis in hepatocellular carcinoma cells.

    Science.gov (United States)

    Sudan, Sudhanshu; Rupasinghe, H P Vasantha

    2014-04-01

    Dietary flavonoids have been associated with reduced risk of cancer including hepatocellular carcinoma (HCC). Quercetin-3-O-glucoside (Q3G) has been shown to possess anti-proliferative and antioxidant activities. The objectives of this study were to assess the anti-proliferative properties of Q3G in human liver cancer cells (HepG2); assess the cytotoxicity on normal primary cells; and elucidate its possible mechanism of action(s). Using a dose- and time-dependent study, we evaluated the antiproliferative properties of Q3G in HepG2 cells using MTS cell viability assay and lactate dehydrogenase release assay. To elucidate the mechanism of action, we performed cell-cycle analysis using flow cytometry. Cell death via apoptosis was analyzed by DNA fragmentation assay, caspase-3 induction assay and fluorescence microscopy. DNA topoisomerase II drug screening assay was performed to assess the effect of Q3G on DNA topoisomerase II. Q3G treatment inhibited cell proliferation in a dose- and time-dependent manner in HepG2 cells with the blockade of the cell cycle in the S-phase. Additionally, Q3G exhibited a strong ability to inhibit DNA topoisomerase II. Furthermore, DNA fragmentation and fluorescence microscopy analysis suggested that Q3G induced apoptosis in HepG2 cells with the activation of caspase-3. Interestingly, Q3G exhibited significantly lower toxicity to normal cells (primary human and rat hepatocytes and primary lung cells) than sorafenib (papoptosis. Further research should be performed to confirm these results in vivo.

  17. Reexpression of ARHI inhibits tumor growth and angiogenesis and impairs the mTOR/VEGF pathway in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Xiaohai; Li, Jinfeng; Zhuo, Jianxin [Department of General Surgery, The Second People' s Hospital of Yueqing, Yueqing 325608 (China); Cai, Liuxin, E-mail: liuxcai08@googlemail.com [Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Linhai 317000 (China)

    2010-12-17

    Research highlights: {yields} Reconstitution of ARHI suppresses the growth of HCC xenografts. {yields} ARHI reexpression impairs tumor angiogenesis in vivo. {yields} Inhibition of the mTOR/VEGF signaling by forced expression of ARHI. {yields} Manipulating ARHI may be of therapeutic benefit in treatment of ARHI-negative HCCs. -- Abstract: The Ras-related tumor suppressor gene aplasia Ras homolog member I (ARHI) is frequently downregulated in many types of cancer, including hepatocellular carcinoma (HCC). In this study, we sought to explore the therapeutic implications of ARHI reconstitution in the treatment of HCC. We generated stable cell lines overexpressing ARHI in Hep3B and SK-Hep1 cells, both of which lack endogenous ARHI. The effects of ARHI reexpression on tumor growth and angiogenesis were assessed. Given the key role of mammalian target of rapamycin (mTOR) signaling in HCC progression, we also tested whether ARHI overexpression affected the mTOR pathway. Forced expression of ARHI resulted in a significant inhibition of the proliferation of both Hep3B and SK-Hep1 cells compared to control cells (P < 0.01). Cell cycle analysis revealed a G0-G1 arrest induced by ARHI reexpression. Moreover, ARHI reexpression significantly retarded Hep3B xenograft growth in vivo, and caused a marked reduction in tumor angiogenesis assessed by CD31-stained microvessel count. Western blot analysis of the xenografts showed that ARHI overexpression substantially reduced the phosphorylation of two mTOR substrates, S6K1 and 4E-BP1, indicative of an inactivation of the mTOR pathway. Accompanying with the mTOR inactivation, the angiogenic factors, hypoxia-inducible factor 1 alpha and vascular endothelial growth factor, were significantly downregulated. These data highlighted an important role for ARHI in controlling HCC growth and angiogenesis, therefore offering a possible therapeutic strategy against this malignancy.

  18. Overexpression of TIMP-1 mediated by recombinant adenovirus in hepatocellular carcinoma cells inhibits proliferation and invasion in vitro

    Institute of Scientific and Technical Information of China (English)

    Dong Xia; Lu-Nan Yan; Jian-Guo Xie; Yu Tong; Mao-Lin Yan; Xin-Ping Wang; Ming-Man Zhang; Lan-Ying Zhao

    2006-01-01

    BACKGROUND: Matrix metalloproteinases (MMPs) and its natural tissue inhibitors of metalloproteinases (TIMPs) are involved in cancer progression. This study was undertaken to determine the effects of overexpression of TIMP-1 on human hepatocellular carcinoma (HCC) cell growth, proliferation, and invasion. METHODS: Employing the efifcient AdEasyTM system, recombinant adenovirus AdTIMP-1 containing full-length cDNA of TIMP-1 was generated by homologous recombination and ampliifed in 293 cells. Then, human HCC cell line (HepG2) underwent gene transfection to overexpress TIMP-1 (so-called HepG-T cells). The mRNA and protein expressions of TIMP-1 were detected with RT-PCR and Western blotting, respectively. The ultrastructure was observed with a transmission electron microscope and the proliferation of HepG-T cells was determined by MTT assay and growth curve. The potential of in vitro invasion was measured with Millicell Chamber. RESULTS:The resulting AdTIMP-1 and HepG-T cells were generated and the expression of TIMP-1 was detected in vitro. The cell proliferation curves and MTT assay showed HepG-T cells' growth, and proliferation were obviously inhibited. The invasion across Matrigel-coated iflters was signiifcantly decreased compared with controls. The suppression rate of HepG-2 cells with AdhTIMP-1 transfection was 50%, and AdhTIMP-1 transfection inhibited by more than 91.6% of the invasion into the Matrigel-coated iflter (P CONCLUSIONS: TIMP-1 overexpression results in the suppression of proliferative and invasive potential of HepG2 cells in vitro. This study demonstrates the potential role of TIMP-1 as a target for liver cancer gene therapy and has laid a foundation for further study on its anticancer function.

  19. miR-613 inhibits the growth and invasiveness of human hepatocellular carcinoma via targeting DCLK1

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Wenyao, E-mail: wangwy117@163.com; Zhang, Hongfei; Wang, Lichao; Zhang, Shaojun; Tang, Miao

    2016-05-13

    microRNAs (miRNAs) play key regulatory roles in various biological processes. In this study, we aimed to determine the expression and biological roles of miR-613 in hepatocellular carcinoma (HCC). Compared with non-cancerous liver tissues, miR-613 was significantly downregulated in HCC tissues. Ectopic expression of miR-613 significantly suppressed the proliferation and invasion of Hep3B and SMMC-7721 HCC cells. Bioinformatic and luciferase reporter analysis identified doublecortin-like kinase 1 (DCLK1) as a direct target of miR-613. Overexpression of miR-613 inhibited the expression of DCLK1 in HCC cells. There was a significant inverse correlation between miR-613 and DCLK1 protein expression in HCC samples. Small interfering RNA-mediated silencing of DCLK1 phenocopied the suppressive effects of miR-613 in HCC cells. Rescue experiments demonstrated that co-transfection of DCLK1 lacking the 3′-untranslated region partially prevented miR-613-induced suppression of HCC cell proliferation and invasion. In vivo studies confirmed that miR-613 overexpression retarded the growth of Hep3B xenograft tumors in nude mice, coupled with a reduction in the percentage of Ki67-positive tumor cells and DCLK1 protein expression. In conclusion, we provide first evidence for the suppressive activity of miR-613 in HCC, which is causally linked to targeting of DCLK1. Restoration of miR-613 may provide a potential therapeutic strategy for HCC. - Highlights: • miR-613 inhibits the aggressive phenotypes of HCC cells. • DCLK1 is a direct target of miR-613 in HCC. • miR-613 impairs HCC tumorigenesis in vivo.

  20. Autophagy inhibition sensitizes KU-0063794-mediated anti-HepG2 hepatocellular carcinoma cell activity in vitro and in vivo.

    Science.gov (United States)

    Yongxi, Tong; Haijun, Huang; Jiaping, Zheng; Guoliang, Shao; Hongying, Pan

    2015-09-25

    Recent studies have indicated that mammalian target of rapamycin (mTOR) signaling has a critical role in the pathogenesis of hepatocellular carcinoma (HCC). In the current study, we investigated the activity of KU-0063794, a novel mTOR kinase inhibitor, against HepG2 HCC cells. Our results demonstrated that KU-0063794 blocked mTOR complex 1/2 (mTORC1/2) activation, and downregulated mTOR-regulated genes (Cyclin D1 and hypoxia-inducible factor 1α) in HepG2 cells. Consequently, KU-0063794 induced significant anti-survival and pro-apoptotic activities against HepG2 cells. When analyzing the possible KU-0063794-resistance factors, we showed that KU-0063794 induced cyto-protective autophagy activation in HepG2 cells, evidenced by GFP-light chain 3B (LC3B) puncta formation, p62 degradation, Beclin-1 expression and LC3B-I to LC3B-II conversion. Correspondingly, autophagy inhibitors, including bafliomycin A1, 3-methyladenine (3-MA) and chloroquine, dramatically enhanced KU-0063794-induced cytotoxicity against HepG2 cells. Further, RNAi knockdown of Beclin-1 also increased KU-0063794 sensitivity in HepG2 cells. In vivo, oral administration of KU-0063794 repressed HepG2 xenograft growth in severe combined immunodeficient (SCID) mice, and its activity was further enhanced with co-administration of the autophagy inhibitor 3-MA. In summary, KU-0063794 inhibits HepG2 cell growth in vitro and in vivo, its activity could be further enhanced with autophagy inhibition. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells.

    Science.gov (United States)

    Fu, Zhi-guang; Wang, Li; Cui, Hong-yong; Peng, Jian-long; Wang, Shi-jie; Geng, Jie-jie; Liu, Ji-de; Feng, Fei; Song, Fei; Li, Ling; Zhu, Ping; Jiang, Jian-li; Chen, Zhi-nan

    2016-02-23

    CD147, a type I transmembrane glycoprotein, is highly expressed in various cancer types and plays important roles in tumor progression, especially by promoting the motility and invasion of hepatocellular carcinoma (HCC) cells. These crucial roles make CD147 an attractive target for therapeutic intervention in HCC, but no small-molecule inhibitors of CD147 have been developed to date. To identify a candidate inhibitor, we used a pharmacophore model derived from the structure of CD147 to virtually screen over 300,000 compounds. The 100 highest-ranked compounds were subjected to biological assays, and the most potent one, dubbed AC-73 (ID number: AN-465/42834501), was studied further. We confirmed that AC-73 targeted CD147 and further demonstrated it can specifically disrupt CD147 dimerization. Moreover, molecular docking and mutagenesis experiments showed that the possible binding sites of AC-73 on CD147 included Glu64 and Glu73 in the N-terminal IgC2 domain, which two residues are located in the dimer interface of CD147. Functional assays revealed that AC-73 inhibited the motility and invasion of typical HCC cells, but not HCC cells that lacked the CD147 gene, demonstrating on-target action. Further, AC-73 reduced HCC metastasis by suppressing matrix metalloproteinase (MMP)-2 via down-regulation of the CD147/ERK1/2/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Finally, AC-73 attenuated progression in an orthotopic nude mouse model of liver metastasis, suggesting that AC-73 or its derivatives have potential for use in HCC intervention. We conclude that the novel small-molecule inhibitor AC-73 inhibits HCC mobility and invasion, probably by disrupting CD147 dimerization and thereby mainly suppressing the CD147/ERK1/2/STAT3/MMP-2 pathways, which are crucial for cancer progression.

  2. [Tumor markers for hepatocellular carcinoma].

    Science.gov (United States)

    Tateishi, Ryosuke; Enooku, Kenichiro; Shiina, Shuichiro; Koike, Kazuhiko

    2012-05-01

    Three tumor markers for hepatocellular carcinoma (HCC) are available in Japan: alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonists-II (PIVKA-II), and Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3). Although AFP has drawbacks in its specificity, it is widely utilized in treatment evaluation and prognosis prediction. PIVKA-II is a unique marker that does not correlate with AFP value and can predict microvascular invasion. AFP-L3 is a highly specific marker and strong predictor of poor prognosis. These three markers are indispensable in every aspect of clinical practice of hepatocellular carcinoma including surveillance, diagnosis, treatment evaluation, and prognosis prediction.

  3. DNA methylation in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Iris Tischoff; Andrea Tannapfel

    2008-01-01

    As for many other tumors, development of hepatocellular carcinoma (HCC) must be understood as a multistep process with accumulation of genetic and epigenetic alterations in regulatory genes, leading to activation of oncogenes and inactivation or loss of tumor suppressor genes (TSG). In the last decades, in addition to genetic alterations, epigenetic inactivation of (tumor suppressor) genes by promoter hypermethylation has been recognized as an important and alternative mechanism in tumorigenesis. In HCC, aberrant methylation of promoter sequences occurs not only in advanced tumors, it has been also observed in premalignant conditions just as chronic viral hepatitis B or C and cirrhotic liver. This review discusses the epigenetic alterations in hepatocellular carcinoma focusing DNA methylation.

  4. Ethyl pyruvate inhibits proliferation and induces apoptosis of hepatocellular carcinoma via regulation of the HMGB1–RAGE and AKT pathways

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Ping; Dai, Weiqi; Wang, Fan; Lu, Jie; Shen, Miao; Chen, Kan; Li, Jingjing; Zhang, Yan; Wang, Chengfen; Yang, Jing; Zhu, Rong; Zhang, Huawei; Zheng, Yuanyuan; Guo, Chuan-Yong, E-mail: guochuanyong@hotmail.com; Xu, Ling, E-mail: xuling606@sina.com

    2014-01-24

    Highlights: • Ethyl pyruvate inhibits liver cancer. • Promotes apoptosis. • Decreased the expression of HMGB1, p-Akt. - Abstract: Ethyl pyruvate (EP) was recently identified as a stable lipophilic derivative of pyruvic acid with significant antineoplastic activities. The high mobility group box-B1 (HMGB1)–receptor for advanced glycation end-products (RAGE) and the protein kinase B (Akt) pathways play a crucial role in tumorigenesis and development of many malignant tumors. We tried to observe the effects of ethyl pyruvate on liver cancer growth and explored its effects in hepatocellular carcinoma model. In this study, three hepatocellular carcinoma cell lines were treated with ethyl pyruvate. An MTT colorimetric assay was used to assess the effects of EP on cell proliferation. Flow cytometry and TUNEL assays were used to analyze apoptosis. Real-time PCR, Western blotting and immunofluorescence demonstrated ethyl pyruvate reduced the HMGB1–RAGE and AKT pathways. The results of hepatoma orthotopic tumor model verified the antitumor effects of ethyl pyruvate in vivo. EP could induce apoptosis and slow the growth of liver cancer. Moreover, EP decreased the expression of HMGB1, RAGE, p-AKT and matrix metallopeptidase-9 (MMP9) and increased the Bax/Bcl-2 ratio. In conclusion, this study demonstrates that ethyl pyruvate induces apoptosis and cell-cycle arrest in G phase in hepatocellular carcinoma cells, plays a critical role in the treatment of cancer.

  5. [Hepatocellular carcinoma. Part 2. Treatment].

    Science.gov (United States)

    Conte, V P

    2000-01-01

    Recent improvements on the therapeutical management of hepatocellular carcinoma are revised with special attention to evaluate the role of surgery for the disease. Considering that definitive surgical intervention is not feasible in most cases because of extreme tumor extension, multiplicity of tumor foci, and associated advanced liver cirrhosis at the time of diagnosis, others forms of treatment are listed, such as transcatheterarterial chemoembolization, percutaneous ethanol and acetic acid injections, and chemotherapy only to a small portion of patients with no indication for standard treatments. The emerging role of retinoic acid metabolism blocking agents, was examined and may offer a significant new potential treatment for cancer, inclusive the possibility of combining other anticancer drugs with exogenous retinoids or modulation of endogenous retinoids as a real opportunity to advance our ability to treat or prevent human cancer effectively Octreotide, nitrosamine and other drugs are analyzed and is concluded that improves survival and is a valuable alternative in the treatment of inoperable hepatocellular carcinoma. The potential role of intersticial laser coagulation for patients with irresectable hepatic tumors was investigated, and in terms of experience, it has now been developed sufficiently to study its effect on these patients survival. The homeostatic control of angiogenesis and its influences on the tumor growth and for migration of metastatic cells, was focused in this concise review, given that hepatocytes are the source of much of the precursor pool, regulation of angiogenesis may be regarded as a new liver function with important consequences for tissue repair and cancer. Early hepatocellular carcinoma and its recognition in routine clinical practice contributes to improved patients survival. Recombinant-Interferon-alpha therapy surely prevents, the development of cirrhosis or hepatocellular carcinoma in about one-third of patients, with

  6. Solanine-induced reactive oxygen species inhibit the growth of human hepatocellular carcinoma HepG2 cells.

    Science.gov (United States)

    Meng, Xue-Qin; Zhang, Wei; Zhang, Feng; Yin, Sheng-Yong; Xie, Hai-Yang; Zhou, Lin; Zheng, Shu-Sen

    2016-03-01

    The aim of the present study was to investigate the effect of solanine on promoting human hepatocellular carcinoma HepG2 cells to produce reactive oxygen species (ROS), and the molecular mechanisms leading to tumor cell apoptosis. Solanine was administered to HepG2 cells in vitro. A selection of probes targeting various cellular localizations of ROS were used to detect ROS expression using flow cytometry. The expression levels of apoptosis-associated proteins, including apoptosis signal-regulating kinase 1 (ASK1) and thioredoxin binding protein 2 (TBP-2), and proliferation-associated proteins, including histone deacetylase 1 (HDAC1), were detected using western blotting. The percentage of cells undergoing apoptosis was measured using an Annexin V-fluorescein isothiocyanate/propidium iodide assay, and cell morphology was examined using Wright's stain followed by inverted microscopy analysis. ROS detection probes 2',7'-dichlorofluorescin diacetate and dihydrorhodamine 123 identified that abundant ROS, including hydroxyl radical (OH(-)) and hydrogen peroxide (H2O2), were produced in the cytoplasm and mitochondria of the solanine-treated HepG2 cells compared with the control cells (Psolanine treatment compared with the control cells (P>0.05). Western blotting results revealed that solanine upregulated the expression levels of ASK1 and TBP-2 and enhanced their kinase activities, whereas solanine decreased the expression level of the proliferation-associated protein, HDAC1. The cell apoptotic rate was significantly increased (Psolanine-treated HepG2 cells compared with the control cells. (Psolanine induces HepG2 cells to produce ROS, mainly OH(-) and H2O2, in a mitochondria-dependent and -independent manner. In addition, solanine stimulates the expression of ASK1 and TBP-2, and their kinase activities, but inhibits the expression of proliferation-associated proteins, such as HDAC1, thus contributing to HepG2 cell apoptosis.

  7. Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis.

    Science.gov (United States)

    Qi, Runzi; An, Huazhang; Yu, Yizhi; Zhang, Minghui; Liu, Shuxun; Xu, Hongmei; Guo, Zhenghong; Cheng, Tao; Cao, Xuetao

    2003-12-01

    Notch signaling plays a critical role in maintaining the balance between cell proliferation, differentiation, and apoptosis; hence, perturbed Notch signaling may contribute to tumorigenesis. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in Africa and Asia. The mechanisms that orchestrate the multiple oncogenic insults required for initiation and progression of HCC are not clear. We constitutively overexpressed active Notch1 in human HCC to explore the effects of Notch1 signaling on HCC cell growth and to investigate the underlying molecular mechanisms. We show here that overexpression of Notch1 was able to inhibit the growth of HCC cells in vitro and in vivo. Biochemical analysis revealed the involvement of cell cycle regulated proteins in Notch1-mediated G(0)/G(1) arrest of HCC cells. Compared with green fluorescent protein (GFP) control, transient transfection of Notch1 ICN decreased expression of cyclin A (3.5-fold), cyclin D1 (2-fold), cyclin E (4.5-fold), CDK2 (2.8-fold), and the phosphorylated form of retinoblastoma protein (3-fold). Up-regulation of p21(waf/cip1) protein expression was observed in SMMC7721-ICN cells stably expressing active Notch1 but not in SMMC7721-GFP cells, which only express GFP. Furthermore, a 12-fold increase in p53 expression and an increase (4.8-fold) in Jun-NH(2)-terminal kinase activation were induced in SMMC7721-ICN cells compared with SMMC7721-GFP cells. In contrast, expression of the antiapoptotic Bcl-2 protein could not be detected in SMMC7721-ICN cells. These findings suggest that Notch1 signaling may participate in the development of HCC cells, affecting multiple pathways that control both cell proliferation and apoptosis.

  8. Inhibition of connective tissue growth factor overexpression decreases growth of hepatocellular carcinoma cells in vitro and in vivo

    Institute of Scientific and Technical Information of China (English)

    JIA Xiao-qin; CHENG Hai-qing; LI Hong; ZHU Yan; LI Yu-hua; FENG Zhen-qing; ZHANG Jian-ping

    2011-01-01

    Background We have previously found that connective tissue growth factor (CTGF) is highly expressed in a rat model of liver cancer.Here,we examined expression of CTGFin human hepatocellular carcinoma (HCC) cells and its effect on cell growth.Methods Real-time PCR was used to observe expression of CTGF in human HCC cell lines HepG2,SMMC-7721,MHCC-97H and LO2.siRNA for the CTGFgene was designed,synthesized and cloned into a Plk0.1-GFP-SP6 vector to construct a lentivirus-mediated shRNA/CTGF.CTGF mRNA and protein expression in HepG2 cells treated by CTGF-specific shRNA was evaluated by real-time PCR and Western blotting.3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was utilized to evaluate the growth effect,and a colony formation assay was used for observing clonogenic growth.In vivo,tumor cell proliferation was evaluated in a nude mouse model of xenotransplantation.Statistical significance was determined by t test for comparison between two groups,or analysis of variance (ANOVA) for multiple groups.Results Immunohistochemical staining of CTGF was seen in 35 of 40 HCC samples (87.5%).CTGF was overexpressed 5-fold in 20 HCC tissues,compared with surrounding non-tumor liver tissue.CTGF mRNA level was 5-8-fold higher in HepG2,SMMC-7721 and MHCC-97H than in LO2 cells.This indicated that the inhibition rate of cell growth was 43% after knockdown of CTGF expression (P <0.05).Soft agar colony formation assay showed that siRNA mediated knockdown of CTGF inhibited colony formation in soft agar of HepG2 cells (P <0.05).The volume of tumors from CTGF-shRNA-expressing cells only accounted for 35% of the tumors from the scrambled control-infected HepG2 cells (P <0.05).Conclusions CTGF was overexpressed in human HCC cells and downregulation of CTGF inhibited HCC growth in vitro and in vivo.Knockdown of CTGF may be a potential therapeutic strategy for treatment of HCC.

  9. Inhibition of hypoxia-inducible carbonic anhydrase-IX enhances hexokinase Ⅱ inhibitor-induced hepatocellular carcinoma cell apoptosis

    Institute of Scientific and Technical Information of China (English)

    Su-jong YU; Hyo-suk LEE; Jung-hwan YOON; Jeong-hoon LEE; Sun-jung MYUNG; Eun-sun JANG; Min-sun KWAK; Eun-ju CHO; Ja-june JANG; Yoon-jun KIM

    2011-01-01

    Aim: The hypoxic condition within large or infiltrative hypovascular tumors produces intracellular acidification, which could activate many signaling pathways and augment cancer cell growth and invasion. Carbonic anhydrase-Ⅸ (CA-Ⅸ) is an enzyme lowering pH. This study is to examine whether hypoxia induces CA-Ⅸ in hepatocellular carcinoma (HCC) cells, and to evaluate its clinical implication in HCC patients.Methods: Human HCC cell lines (Huh-7 and HepG2 cells) were used, and cell growth was assessed using MTS assay. CA-IX expression and apoptotic/kinase signaling were evaluated using immunoblotting. The cells were transfected with CA-Ⅸ-specific siRNA, or treated with its inhibitor 4-(2-aminoethyl) benzenesulfonamide (CAI#1), and/or the hexokinase Ⅱ inhibitor, 3-bromopyruvate (3-BP). A clinic pathological analysis of 69 patients who underwent an HCC resection was performed using a tissue array.Results: Incubation of HCC cells under hypoxia (1% 02, 5% C02, 94% N2) for 36 h significantly increased CA-IX expression level. CAI#1(400 μmol/L) or CA-IX siRNA (100 μmol/L) did not influence HCC cell growth and induce apoptosis. However, CAI#1 or CA-IX siRNA at these concentrations enhanced the apoptosis induced by 3-BP (100 μmol/L). This enhancement was attributed to increased ER stress and JNK activation, as compared with 3-BP alone. Furthermore, a clinic pathological analysis of 69 HCC patients revealed that tumor CA-Ⅸ intensity was inversely related to E-cadherin intensity.Conclusion: Inhibition of hypoxia-induced CA-Ⅸ enhances hexokinase Ⅱ inhibitor-induced HCC apoptosis. Furthermore, CA-IX expres sion profiles may have prognostic implications in HCC patients. Thus, the inhibition of CA-Ⅸ, in combination with a hexokinase Ⅱ inhibitor, may be therapeutically useful in patients with HCCs that are aggressively growing in a hypoxic environment.

  10. Management of large hepatocellular carcinoma.

    Science.gov (United States)

    Amarapurkar, D N

    2004-04-01

    Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. There is increasing incidence of HCC in India. More than 70% of HCC are not suitable for curative treatment. Majority of the HCCs are large when diagnosed all over the world. There is no standard treatment for large HCCs. Different palliative treatments like arterial embolization/chemoembolization, intraarterial lipoidol chemotherapy, hormonal compounds like tamoxifene, octerotide systemic chemotherapy, immuno therapy with interferon, internal radiation with 131I or 99Yttrium. Arterial chemoembolization is the treatment of choice with proved efficacy in selected group of patients. The newer modalities and strategies need to be tried in controlled randomized trials.

  11. Oncogenic viruses and hepatocellular carcinoma.

    Science.gov (United States)

    Ben Ari, Ziv; Weitzman, Ella; Safran, Michal

    2015-05-01

    About 80% of hepatocellular carcinoma (HCC) is caused by hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections especially in the setting of established cirrhosis or advanced fibrosis, making HCC prevention a major goal of antiviral therapy. HCC tumors are highly complex and heterogeneous resulting from the aberrant function of multiple molecular pathways. The roles of HCV or HBV in promoting HCC development are still either directly or indirectly are still speculative, but the evidence for both effects is compelling. In patients with chronic hepatitis viral infection, cirrhosis is not a prerequisite for tumorigenesis.

  12. Genetic alteration in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yoo Chul; Kang, Tae Woong; Lee, Jin Oh [Korea Cancer Center Hospital of Korea Atomic Energy Research Institute, Seoul (Korea, Republic of)

    1994-12-01

    Cancer of stomach, colon and liver are a group of the most common cancer in Korea. However, results with current therapeutic modalities are still unsatisfactory. The intensive efforts have been made to understand basic pathogenesis and to find better therapeutic tools for the treatment of this miserable disease. We studied the alteration of tumor suppressor genes and oncogenes in hepatocellular carcinoma in Korea. We found that alteration of Rb gene, APC were 33 %, 13 % respectively. But alterations of oncogenes such as myc, ras and mdm2 were rarely found. Our results suggests that HBV may act as oncogenic role in hepatocarcinogenesis instead of oncogenes. 6 figs, 2 tabs. (Author).

  13. Transhemangioma Ablation of Hepatocellular Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Pua, Uei, E-mail: druei@yahoo.com [Tan Tock Seng Hospital, Department of Diagnostic Radiology (Singapore)

    2012-12-15

    Radiofrequency ablation (RFA) is a well-established treatment modality in the treatment of early hepatocellular carcinoma (HCC) [1]. Safe trajectory of the RFA probe is crucial in decreasing collateral tissue damage and unwarranted probe transgression. As a percutaneous technique, however, the trajectory of the needle is sometimes constrained by the available imaging plane. The presence of a hemangioma beside an HCC is uncommon but poses the question of safety related to probe transgression. We hereby describe a case of transhemangioma ablation of a dome HCC.

  14. TIPE2 inhibits TNF-α-induced hepatocellular carcinoma cell metastasis via Erk1/2 downregulation and NF-κB activation.

    Science.gov (United States)

    Zhang, Yue Hua; Yan, Hong Qiong; Wang, Fang; Wang, Yan Yan; Jiang, Yi Na; Wang, Yi Nan; Gao, Feng Guang

    2015-01-01

    Tumor necrosis factor-α-induced protein 8-like 2 (TNFAIP8L2, TIPE2), which belongs to the TNF-α-induced protein 8 family, is a negative regulator of immune homeostasis. Although pro-inflammatory cytokines such as TNF-α have been reported to be involved in liver carcinoma metastasis, the effect of TIPE2 on hepatocellular carcinoma metastasis remains unknown. We demonstrate that TNF-α clearly augments MMP-13/MMP-3 expression and promotes cell migration in HepG2 cells through activation of the Erk1/2-NF-κB pathways. Interestingly, in addition to human PBLs, macrophages and fibroblasts, liver cancer cells specifically express TNF-α following LPS treatment. Most importantly, TIPE2 overexpression efficiently abrogates the effects of LPS on TNF-α secretion and abolishes the effects of TNF-α on MMP-13/MMP-3 upregulation, cell migration and Erk1/2-NF-κB activation. Taken together, these findings demonstrate that TIPE2 was able to suppress TNF-α-induced hepatocellular carcinoma metastasis by inhibiting Erk1/2 and NF-κB activation, indicating that both TNF-α and TIPE2 might be potential targets for the treatment of HCC metastasis.

  15. Surgical Treatment for Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Ahmad A Madkhali

    2015-01-01

    Full Text Available Hepatocellular carcinoma (HCC is an epithelial tumor derived from hepatocytes; it accounts for 80% of all primary liver cancers and ranks globally as the fourth leading cause of cancer-related deaths. HCC treatment is a multidisciplinary and a multimodal task, with surgery in the form of liver resection and liver transplantation (LT representing the only potentially curative modality. However, there are variable opinions and discussions about applying these surgical options and using other supporting treatments. This article is a narrative review that includes articles published from 1984 to 2013 located by searching scientific databases such as PubMed, SCOPUS, and Elsevier, with the main keyword of hepatocellular carcinoma in addition to other keywords such as liver transplantation, liver resection, transarterial chemoembolization, portal vein embolization, bridging therapy, and downstaging. In this review, we focus mainly on the surgical treatment options offered for HCC, in order to illustrate the current relevant data available in the literature to help in applying these surgical options and to use other supporting treatment modalities when appropriate.

  16. Protein arginine N-methyltransferase 1 promotes the proliferation and metastasis of hepatocellular carcinoma cells.

    Science.gov (United States)

    Gou, Qing; He, ShuJiao; Zhou, ZeJian

    2017-02-01

    Hepatocellular carcinoma is the most common subtype of liver cancer. Protein arginine N-methyltransferase 1 was shown to be upregulated in various cancers. However, the role of protein arginine N-methyltransferase 1 in hepatocellular carcinoma progression remains incompletely understood. We investigated the clinical and functional significance of protein arginine N-methyltransferase 1 in a series of clinical hepatocellular carcinoma samples and a panel of hepatocellular carcinoma cell lines. We performed suppression analysis of protein arginine N-methyltransferase 1 using small interfering RNA to determine the biological roles of protein arginine N-methyltransferase 1 in hepatocellular carcinoma. In addition, the expression of epithelial-mesenchymal transition indicators was verified by western blotting in hepatocellular carcinoma cell lines after small interfering RNA treatment. Protein arginine N-methyltransferase 1 expression was found to be significantly upregulated in hepatocellular carcinoma cell lines and clinical tissues. Moreover, downregulation of protein arginine N-methyltransferase 1 in hepatocellular carcinoma cells by small interfering RNA could inhibit cell proliferation, migration, and invasion in vitro. These results indicate that protein arginine N-methyltransferase 1 may contribute to hepatocellular carcinoma progression and serves as a promising target for the treatment of hepatocellular carcinoma patients.

  17. Nonalcoholic steatohepatitis and hepatocellular carcinoma: Brazilian survey

    Directory of Open Access Journals (Sweden)

    Helma P. Cotrim

    2016-05-01

    Full Text Available OBJECTIVE: The majority of cases of hepatocellular carcinoma have been reported in individuals with cirrhosis due to chronic viral hepatitis and alcoholism, but recently, the prevalence has become increasingly related to nonalcoholic steatohepatitis around the world. The study aimed to evaluate the clinical and histophatological characteristics of hepatocellular carcinoma in Brazilians' patients with nonalcoholic steatohepatitis at the present time. METHODS: Members of the Brazilian Society of Hepatology were invited to complete a survey regarding patients with hepatocellular carcinoma related to nonalcoholic steatohepatitis. Patients with a history of alcohol intake (>20 g/day and other liver diseases were excluded. Hepatocellular carcinoma diagnosis was performed by liver biopsy or imaging methods according to the American Association for the Study of Liver Diseases’ 2011 guidelines. RESULTS: The survey included 110 patients with a diagnosis of hepatocellular carcinoma and nonalcoholic fatty liver disease from nine hepatology units in six Brazilian states (Bahia, Minas Gerais, Rio de Janeiro, São Paulo, Paraná and Rio Grande do Sul. The mean age was 67±11 years old, and 65.5% were male. Obesity was observed in 52.7% of the cases; diabetes, in 73.6%; dyslipidemia, in 41.0%; arterial hypertension, in 60%; and metabolic syndrome, in 57.2%. Steatohepatitis without fibrosis was observed in 3.8% of cases; steatohepatitis with fibrosis (grades 1-3, in 27%; and cirrhosis, in 61.5%. Histological diagnosis of hepatocellular carcinoma was performed in 47.2% of the patients, with hepatocellular carcinoma without cirrhosis accounting for 7.7%. In total, 58 patients with cirrhosis had their diagnosis by ultrasound confirmed by computed tomography or magnetic resonance imaging. Of these, 55% had 1 nodule; 17%, 2 nodules; and 28%, ≥3 nodules. CONCLUSIONS: Nonalcoholic steatohepatitis is a relevant risk factor associated with hepatocellular carcinoma in

  18. Xanthohumol, a prenylated chalcone derived from hops, inhibits proliferation, migration and interleukin-8 expression of hepatocellular carcinoma cells.

    Science.gov (United States)

    Dorn, Christoph; Weiss, Thomas S; Heilmann, Jörg; Hellerbrand, Claus

    2010-02-01

    Xanthohumol, the major prenylated chalcone found in hops, is well known to exert anti-cancer effects, but information regarding the impact on hepatocellular carcinoma (HCC) cells and potential adverse effects on non-tumorous hepatocytes is limited. Here, we show that xanthohumol at a concentration of 25 microM induced apoptosis in two HCC cell lines (HepG2 and Huh7). Furthermore, xanthohumol repressed proliferation and migration, as well as TNF induced NF-kappaB activity and interleukin-8 expression in both cell lines at even lower concentrations. In contrast, xanthohumol concentrations up to 100 microM did not affect viability of primary human hepatocytes in vitro. In summary, our data showed that xanthohumol can ameliorate different pro-tumorigenic mechanisms known to promote HCC progression, indicating its potential as promising therapeutic agent that selectively affects cancer cells.

  19. Methylation in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Regina M. Santella

    2007-02-01

    Full Text Available

    The development of HCC is a complex, multistep, multistage process. The molecular pathogenesis of HCC appears to involve multiple genetic aberrations in the molecular control of hepatocyte proliferation, differentiation and death and the maintenance of genomic integrity. This process is influenced by the cumulative activation and inactivation of oncogenes, tumor suppressor genes and other genes. p53, a tumor suppressor gene, is the most frequently mutated gene in human cancers. There is also a striking sequence specific binding and induction of mutations by AFB1 at codon 249 of p53 in HCC.

    Epigenetic alterations are also involved in cancer development and progression. Methylation of promoter CpG islands is associated with inhibition of transcriptional initiation and permanent silencing of downstream genes.

    It is now known that most important tumor suppressor genes are inactivated, not only by mutations and deletions but also by promoter methylation. Several studies indicated that p16, p15, RASSF1A, MGMT, and GSTP1 promoter hypermethylation are prevalent in HCC. In addition, geographic variation in the methylation status of tumor DNA indicates that environmental factors may influence the frequent and concordant degree of hypermethylation in multiple genes in HCC and that epigeneticenvironmental interactions may be involved in hepatocarcinogenesis. We have found significant relationships between promoter methylation and AFB1-DNA adducts confirming the impact of environmental exposures on gene methylation.

    DNA isolated from serum or plasma of cancer patients frequently contains the same genetic and

  20. Hepatocellular carcinoma and industrial epidemics

    Institute of Scientific and Technical Information of China (English)

    Alain Braillon; Gérard Dubois

    2011-01-01

    Worldwide, the burden of the non viral causes of hepatocellular carcinoma (HCC) is usually underestimated. Clearly industrial goods, tobacco, alcohol and processed foods are the agents of new epidemics in modern times which far outscore the burden of infectious agents on morbidity and mortality. Smoking, a dose-related contributing factor for HCC, receives too little attention in clinical practice. In France, tobacco, hepatitis B and C virus and alcohol are the main risk factors for HCC mortality (33%, 31% and 26%, respectively). In developing countries, where tobacco consumption is dramatically increasing, this epidemic may soon surpass hepatitis B. Obesity and diabetes are the contributing factors too. The role of industrial processed foods in the increase of the prevalence of obesity and diabetes cannot be ignored.

  1. Transarterial Therapies for Hepatocellular Carcinoma

    Science.gov (United States)

    Lanza, Ezio; Donadon, Matteo; Poretti, Dario; Pedicini, Vittorio; Tramarin, Marco; Roncalli, Massimo; Rhee, Hyungjin; Park, Young Nyun; Torzilli, Guido

    2016-01-01

    Background The treatment of hepatocellular carcinoma (HCC) is still a major health issue because of its increasing incidence and because of the complexity of its management. Transarterial embolization (TAE) and transarterial chemoembolization (TACE) are two widely used locoregional therapies in the treatment of HCC, especially for unresectable intermediate and advanced HCCs. Summary The modern use of TAE and TACE opens new scenarios for the treatment of unresectable HCC and has yielded interesting results. The present work describes the role of transarterial therapies for HCC and focuses on the different Western and Eastern approaches to the study of response predictors. Key Messages Recent refinements in interventional radiology techniques and in HCC patient selection have facilitated better local control of the disease. The molecular profiling of HCC to predict the response to TACE and TAE will greatly help clinicians identify the optimum therapy. PMID:27995085

  2. STUDY ON THE EXPRESSION OF CYCLOOXYGENASE-2 IN HEPATOCELLULAR CARCINOMA CELL LINES AND ON THE GROWTH INHIBITION EFFECT OF NS-398

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Objective: To investigate the expression of cyclooxygenase -2 (COX-2) in hepatocellular carcinoma cell lines and to explore the effect of NS-398, a selective inhibitor for COX-2, on HepG-2 cell line. Methods: Immunohistochemistry and RT-PCR were used to investigate COX-2 expression in 6 HCC cell lines. MTT and Flowcytometry were used to evaluate the effect of the selective inhibitor of COX-2, NS-398, on HepG-2 cell lines. Results: All six HCC cell lines showed COX-2 expression at protein level. Five out of 6 cell lines showed COX-2 expression at mRNA level. NS-398 could suppress the growth of HepG-2 cell line, in a time and dose dependant manner. Conclusion: NS-398, a selective inhibitor of COX-2, showed inhibition effect on HepG-2 HCC cell line. The efficacy of inhibition was time and dose dependent, providing a new evidence for chemoprovention of hepatocellular carcinorma with COX-2 selective inhibitors.

  3. Advances in hepatocellular carcinoma: Nonalcoholic steatohepatitis-related hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Fauzia; Z; Khan; Ryan; B; Perumpail; Robert; J; Wong; Aijaz; Ahmed

    2015-01-01

    An increase in the prevalence of obesity and diabetes mellitus has been associated with the rise in non-alcoholic fatty liver disease(NAFLD). Two-thirds of the obese and diabetic populations are estimated to develop NAFLD. Currently, NAFLD is the most common etiology for chronic liver disease globally. The clinical spectrum of NAFLD ranges from simple steatosis, an accumulation of fat greater than 5% of liver weight, to nonalcoholic steatohepatitis(NASH), a more aggressive form with necroinflammation and fibrosis. Among the patients who develop NASH, up to 20% may advance to cirrhosis and are at risk for complications of end-stage liver disease. One of the major complications observed in patients with NASH-related cirrhosis is hepatocellular carcinoma(HCC), which has emerged as the sixth most common cancer and second leading etiology of cancer-related deaths worldwide. The incidence of HCC in the United States alone has tripled over the last three decades. In addition, emerging data are suggesting that a small proportion of patients with NAFLD may be at higher risk for HCC in the absence of cirrhosis - implicating obesity and diabetes mellitus as potential risk factors for HCC.

  4. Viral hepatitis and hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Francque Sven M

    2005-05-01

    Full Text Available Abstract Background Hepatocellular carcinoma (HCC is one of the most common malignant tumors in the world. The incidence of HCC varies considerably with the geographic area because of differences in the major causative factors. Chronic hepatitis B and C, mostly in the cirrhotic stage, are responsible for the great majority of cases of HCC worldwide. The geographic areas at the highest risk are South-East Asia and sub-Saharan Africa, here hepatitis B is highly endemic and is the main cause of HCC. In areas with an intermediate rate of HCC such as Southern Europe and Japan, hepatitis C is the predominant cause, whereas in low rate areas such as Northern Europe and the USA, HCC is often related to other factors as alcoholic liver disease. There is a rising incidence in HCC in developed countries during the last two decades, due to the increasing rate of hepatitis C infection and improvement of the clinical management of cirrhosis. Methods This article reviews the literature on hepatitis and hepatocellular carcinoma. The Medline search was carried out using these key words and articles were selected on epidemiology, risk factors, screening, and prevention of hepatocellular carcinoma. Results Screening of patients with advanced chronic hepatitis B and C with hepatic ultrasound and determination of serum alfa-fetoprotein may improve the detection of HCC, but further studies are needed whether screening improves clinical outcome. Hepatitis B and C viruses (HBV/HCV can be implicated in the development of HCC in an indirect way, through induction of chronic inflammation, or directly by means of viral proteins or, in the case of HBV, by creation of mutations by integration into the genome of the hepatocyte. Conclusion The most effective tool to prevent HCC is avoidance of the risk factors such as viral infection. For HBV, a very effective vaccine is available. Preliminary data from Taiwan indicate a protective effect of universal vaccination on the

  5. C/EBPα Short-Activating RNA Suppresses Metastasis of Hepatocellular Carcinoma through Inhibiting EGFR/β-Catenin Signaling Mediated EMT.

    Directory of Open Access Journals (Sweden)

    Hongbo Huan

    Full Text Available Hepatocellular carcinoma is associated with high mortality, and tumor metastasis is an important reason for poor prognosis. However, metastasis has not been effectively prevented in clinical therapy and the mechanisms underlying metastasis have not been fully characterized. CCAAT/enhancer-binding protein-α (C/EBPα is a transcriptional regulator with an essential role in tumor metastasis. We used short-activating RNAs (saRNA to enhance expression of C/EBPα. Intravenous injection of C/EBPα-saRNA in a nude mouse liver orthotopic xenograft tumor model inhibited intrahepatic and distant metastasis. C/EBPα-saRNA-treated mice showed increased serum levels of albumin and decreased alanine aminotransferase (ALT, glutamic-oxalacetic transaminase (AST, indicating a role of C/EBPα in improving liver function. Migration and invasion were inhibited in hepatoma cell lines transfected with C/EBPα-saRNA. We also observed an inhibition of epithelial-mesenchymal transition (EMT and suppression of epidermal growth factor receptor (EGFR, EGFR phosphorylation, and β-catenin in C/EBPa-saRNA-transfected cells. Our results suggested that C/EBPα-saRNA successfully inhibited HCC metastasis by inhibiting EGFR/β-catenin signaling pathway mediated EMT in vitro and in vivo.

  6. Metastatic Hepatocellular Carcinoma Responsive to Pembrolizumab.

    Science.gov (United States)

    Truong, Phu; Rahal, Ahmad; Kallail, K James

    2016-01-01

    Hepatocellular carcinoma (HCC) is an aggressive liver tumor that occurs with chronic liver disease. Surgical resection is the mainstay of therapy for localized disease whereas therapeutic options for advanced disease are limited. The innovative blockade of immune checkpoints with targeted immunotherapies, such as monoclonal antibodies against programmed death receptor 1 (PD-1), have shown promise in the treatment of solid malignancies. The PD-1 inhibiting antibodies, nivolumab and pembrolizumab prolonged overall survival in randomized trials in metastatic melanoma and advanced non-small cell lung cancer. This is a report of a 75-year-old male patient with metastatic HCC who was initially treated with the standard of therapy sorafenib. After failure of sorafenib therapy, pembrolizumab was started. There was a dramatic response to pembrolizumab with decrease in tumor size and drop in alfa fetoprotein. To the best of our knowledge, this is the first case report of metastatic HCC responsive to pembrolizumab after failure of sorafenib.

  7. Lentivirally engineered dendritic cells activate AFP-specific T cells which inhibit hepatocellular carcinoma growth in vitro and in vivo.

    Science.gov (United States)

    Liu, Yang; Butterfield, Lisa H; Fu, Xiaohui; Song, Zhenshun; Zhang, Xiaoping; Lu, Chongde; Ding, Guanghui; Wu, Mengchao

    2011-07-01

    α-fetoprotein (AFP), a tumor-associated antigen for hepatocellular carcinoma (HCC), is an established biomarker for HCC. In this study, we created a lentivirus expressing the AFP antigen and investigated the anti-tumor activity of AFP-specific CD8+ T cells, with and without CD4+ T cells, which were activated by either AFP peptide-pulsed or Lenti-AFP-engineered Dendritic cells (DCs) in vitro and in vivo. AFP-specific T cells could efficiently kill HepG2 HCC cells, and produced IL-2, IFN-γ, TNF-α, perforin and granzyme B, with minimal production of IL-10 (a negative regulator of T cell activation). Both strategies activated AFP-specific T cells, but the lentiviral strategy was superior by several measures. Data also support an impact of CD4+ T cells in supporting anti-tumor activity. In vivo studies in a xenograft HCC tumor model also showed that AFP-specific T cells could markedly suppress HCC tumor formation and morbidity in tumor-bearing nude mice, as well as regulate serum levels of related cytokines and anti-tumor molecules. In parallel with human in vitro T cell cultures, the in vivo model demonstrated superior anti-tumor effects and Th1-skewing with Lenti-AFP-DCs. This study supports the superiority of a full-length antigen lentivirus-based DCs vaccine strategy over peptides, and provides new insight into the design of DCs-based vaccines.

  8. Knockdown of the differentially expressed gene TNFRSF12A inhibits hepatocellular carcinoma cell proliferation and migration in vitro

    Science.gov (United States)

    Wang, Tao; Ma, Sicong; Qi, Xingxing; Tang, Xiaoyin; Cui, Dan; Wang, Zhi; Chi, Jiachang; Li, Ping; Zhai, Bo

    2017-01-01

    Human hepatocellular carcinoma (HCC) has been reported to be highly insensitive to conventional chemotherapy. In the current study, the Agilent Whole Human Genome Oligo Microarray (4×44 K) was used in order to identify the differentially expressed genes between HCC and adjacent tissues, and the top 22 differentially expressed genes were confirmed through reverse transcription-quantitative polymerase chain reaction. Among the identified differences in gene expression, expression of tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) was markedly higher in HCC tissue than in adjacent tissue. Previous studies have suggested that TNFRSF12A may serve a role in tumor growth and metastasis, thus in the current study, TNFRSF12A was knocked down in the SMMC7721 cell line through siRNA. This demonstrated that cells exhibited reduced reproductive and metastatic capacity ex vivo. Thus, the results of the current study suggest that TNFRSF12A may be a candidate therapeutic target for cancer including HCC, and additional genes that exhibited significantly different expression from normal adjacent tissues require further study. PMID:28138696

  9. Serine protease inhibitor kazal-type 6 inhibits tumorigenesis of human hepatocellular carcinoma cells via its extracellular action

    Science.gov (United States)

    Wang, Wei; Gu, Meigang; Dai, Xinchuan; Xu, Yuqiang; Wu, Hongyu; Li, Guodong; Lu, Hairong; Zhong, Jiang; Huang, Qingshan

    2017-01-01

    Hepatocellular carcinoma (HCC) causes significant medical burdens worldwide. Diagnosis, especially in the early stages, is still challenging. Therapeutic options are limited and often ineffective. Although several risk factors have been known important for development of HCC, the molecular basis of the process is rather complex and has not been fully understood. We have found that a subpopulation of HCC cells which are resistant to oncolytic parvovirus H1 superinfection highly express serine protease inhibitor Kazal-type 6 (SPINK6). This protein is specifically reduced in all HCC cell lines and tissues we analyzed. When upregulated, SPINK6 could suppress the malignant phenotypes of the HCC cells in several in vitro models. The putative tumor suppression role of SPINK6 is, however, independent of its protease inhibitory activity. To suppress the malignancy of HCC cells, SPINK6 has to be secreted to trigger signals which regulate an intracellular signaling molecule, ERK1/2, as well as a series of downstream factors involved in cell cycle progression, apoptosis and migration. Our study supports that SPINK6 is an important tumor suppressor in liver, and further investigations may help develop more effective diagnostic and therapeutic approaches. PMID:27999203

  10. Inhibition of tumor growth and metastasis with antisense oligonucleotides(Cantide) targeting hTERT in an in situ human hepatocellular carcinoma model

    Institute of Scientific and Technical Information of China (English)

    Ru-xian LIN; Chao-wei TUO; Qiu-jun L(u); Wei ZHANG; Sheng-qi WANG

    2005-01-01

    Aim: To evaluate the in vivo antitumor effects of Cantide and the combined effect with 5-fluorouracil. Methods: An in situ human hepatocellular carcinoma model was established in mice livers orthotopically. Drugs were administered intravenously and tumor sizes were monitored with calipers. Plasma alpha-fetoprotein (AFP) were detected by radiation immunoassay. Morphology of tumors was evaluated by hematoxylin-eosin (H&E) staining of histological sections. Human telomerase reverse transcriptase (hTERT) protein levels were detected by Western blotting. Results: Cantide significantly inhibit in situ human hepatocellular compared to the saline group in a dose-dependent manner, which included injectthe tumor in liver. Cantide was also found to prevent tumor recurrence in the liver and metastasis in the lung, showing a dose-dependent response. When Cantide was administered by iv combined with 5-fluorouracil, it resulted in a significant reduction in tumor growth compared to either agent alone treatment group. After the treatment with Cantide alone or combined with 5-fluorouracil, plasma AFP concentration decreased in a dose-dependent manner. Conclusion: These results demonstrated that Cantide was an effective antitumor antisense oligonucleotide in vivo and has the potential to be developed into a clinical anti-cancer drug.

  11. Second laparoscopic resection for recurrent hepatocellular carcinoma after initial laparoscopic

    Institute of Scientific and Technical Information of China (English)

    LIANG Xiao; CAI Xiu-jun; YU Hong; WANG Yi-fan; LIANG Yue-long

    2009-01-01

    @@ With the development of laparoscopic techniques,laparoscopic hepatectomy is feasible for hepatocellular carcinoma as reported in recent years.Although several reports have been published on laparoscopic surgery for metastatic liver cancer,1,2 few of them deals with second laparoscopic resection of recurrent hepatocellular carcinoma. We report a case of second laparoscopic resection for recurrent hepatocellular carcinoma after initial laparoscopic hepatectomy.

  12. [Viruses and primary hepatocellular carcinoma].

    Science.gov (United States)

    Jablonská, M

    1997-10-22

    The etiological association between primary hepatocellular carcinoma (PHCC) and chronic viral hepatitis has been proved by now beyond doubt in the hepatitis B virus (HBV) and C virus (HCV). PHCC develops most frequently in cirrhotic livers, sometimes also in the absence of cirrhosis. Extensive epidemiological studies provided convincing evidence of this etiological relationship which is also supported by observations and animal experiments. An important factor in hepatocarcinogenesis due to the influence of HBV is integration of the viral genoma into the liver cell genoma. In the tumourous part of the liver integrated HBV sequences are more frequent than in the non-tumourous part. The integration can produce changes in the genome of the liver cell which may sometimes lead to malignant transformation. The mechanisms of this process are not quite clear so far. Their outcome--the development of carcinoma--can be summarized as the peak effect of factors leading to the disorganization of DNA with participation of chromosomal changes, the action of transactivation of HBs protein, transformation growth factors and the important influence of mutations of the suppressor gene p 53 on the 17th chromosome which is probably the target of HBV. HCV produces chronic live: disease developing into cirrhosis and PHCC, even more frequent than HBV; however its integration into the liver cell does not take place. The genetic variability of this gene is great. Its transformating action is probably implemented rather as a co-carcinogen on the background of cirrhosis of the liver which alone regardless of its cause is an increased risk for the development of PHCC. In clinical practice these findings imply the necessity of optimal prevention of chronic viral hepatic infection (vaccination, so far available for HBV, transfusions) and the necessity to assess the virological status in patients with chronic liver disease and early detection of small tumourous liver lesions where nowadays due to

  13. Surgical management of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Tony CY Pang; Vincent WT Lam

    2015-01-01

    Hepatocellular carcinoma (HCC) is the second mostcommon cause of death from cancer worldwide.Standard potentially curative treatments are eitherresection or transplantation. The aim of this paper isto provide an overview of the surgical managementof HCC, as well as highlight current issues in hepaticresection and transplantation. In summary, due to therelationship between HCC and chronic liver disease,the management of HCC depends both on tumourrelatedand hepatic function-related considerations. Assuch, HCC is currently managed largely through nonsurgicalmeans as the criteria, in relation to the aboveconsiderations, for surgical management is still largelyrestrictive. For early stage tumours, both resectionand transplantation offer fairly good survival outcomes(5 years overall survival of around 50%). Selectiontherefore would depend on the level of hepatic functionderangement, organ availability and local expertise.Patients with intermediate stage cancers have limitedoptions, with resection being the only potential forcure. Otherwise, locoregional therapy with transarterialchemoembolization or radiofrequency ablation are viableoptions. Current issues in resection and transplantationare also briefly discussed such as laparoscopic resection,ablation vs resection, anatomical vs non-anatomicalresection, transplantation vs resection, living donor livertransplantation and salvage liver transplantation.

  14. Targeted therapies in hepatocellular carcinoma.

    Science.gov (United States)

    Bronte, F; Bronte, G; Cusenza, S; Fiorentino, E; Rolfo, C; Cicero, G; Bronte, E; Di Marco, V; Firenze, A; Angarano, G; Fontana, T; Russo, A

    2014-01-01

    The onset of hepatocellular carcinoma (HCC) is related to the development of non-neoplastic liver disease, such as viral infections and cirrhosis. Even though patients with chronic liver diseases undergo clinical surveillance for early diagnosis of HCC, this cancer is often diagnosed in advanced stage. In this case locoregional treatment is not possible and systemic therapies are the best way to control it. Until now sorafenib, a Raf and multi-kinase inhibitor has been the best, choice to treat HCC systemically. It showed a survival benefit in multicenter phase III trials. However the proper patient setting to treat is not well defined, since the results in Child-Pugh B patients are conflicting. To date various new target drugs are under developed and other biological treatments normally indicated in other malignancies are under investigation also for HCC. These strategies aim to target the different biological pathways implicated in HCC development and progression. The target drugs studied in HCC include anti-VEGF and anti-EGFR monoclonal antibodies, tyrosine kinase inhibitors and mTOR inhibitors. The most important challenge is represented by the best integration of these drugs with standard treatments to achieve improvement in overall survival and quality of life.

  15. Interventional treatments for hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Yong-Song Guan; Yuan Liu

    2006-01-01

    BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most frequent primary malignant tumors in the world. Hepatic resection and liver transplantation are considered optimal for potential treatment of HCC. However, only 20%of HCCs can be surgically treated. And most of surgically-noneligible patients have to receive interventional managements including local ablation and transarterial chemoembolization (TACE). In this paper, we review the interventional treatments of HCC. DATA SOURCES:A literature search of PubMed database was conducted and research articles were reviewed. RESULTS: Percutaneous ethanol injection (PEI) is usually applied to small HCC for a complete necrosis. Radiofrequency ablation, an alternative to PEI, also causes tumor necrosis and needs fewer times of ablation. Other methods such as acetic acid injection, laser, microwave, etc have enriched local ablation for HCC. High intensity focus ultrasound (HIFU) is thought to be promising. TACE, another common modality, can improve the survival rate of patients with HCC. The newly developed embolic agents and adjuvant rAd-p53 gene therapy are well reported. CONCLUSIONS:Surgically-noneligible HCC can be treated with interventional procedures. Each method has its advantages and disadvantages. However, it is still pressing to develop ablative methods as well as new embolic agents for a better prognosis of HCC.

  16. Diosmetin inhibits cell proliferation and induces apoptosis by regulating autophagy via the mammalian target of rapamycin pathway in hepatocellular carcinoma HepG2 cells.

    Science.gov (United States)

    Liu, Jie; Ren, Hao; Liu, Bin; Zhang, Qingyu; Li, Mingyi; Zhu, Runzhi

    2016-12-01

    Hepatocellular carcinoma (HCC), which is a type of malignant tumor, is the fifth most common cancer in men and ninth in women worldwide. The aim of the present study was to investigate the antitumor effect of diosmetin (DIOS) in hepatocellular carcinoma HepG2 cells. The proliferation, apoptosis and autophagy rates of HepG2 cells were measured following treatment with DIOS. The effects of DIOS treatment on HepG2 cell proliferation and apoptosis rates were analyzed using MTT assays and Annexin V staining, respectively. The effect of DIOS treatment on autophagy levels was assessed using transmission electron microscopy, green fluorescent protein (GFP)-microtubule-associated protein 1 light chain (LC3) transfection and LysoTracker Red staining. Furthermore, bafilomycin A1 (BA1), an autophagy inhibitor, was used to assess the association between DIOS and cell autophagy, proliferation and apoptosis. In addition, the expression of autophagy-related proteins [mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase, P70S6K, phosphoinositide-dependent kinase-1, extracellular signal-regulated kinase, 5'-AMP-activated protein kinase and Akt] and apoptosis-related proteins [B-cell lymphoma (Bcl)-2-associated X protein, Bak, p53, Bcl-2 and caspase-3] were analyzed by western blotting. The results revealed that DIOS significantly inhibited proliferation (PHepG2 cells. It was also demonstrated that DIOS triggered autophagy by regulating the mTOR pathway in HepG2 cells. Notably, following treatment of HepG2 cells with the autophagy inhibitor, BA1, the expression of apoptosis-related proteins, including Bax, Bak and p53, were significantly decreased (PHepG2 cells via regulation of the mTOR pathway. Thus, the results of the current study indicate that DIOS may present a potential therapeutic agent for HCC treatment.

  17. Inhibition of adhesion and metastasis of HepG2 hepatocellular carcinoma cells in vitro by DNA aptamer against sialyl Lewis X.

    Science.gov (United States)

    Wang, Xiao-Kang; Peng, Yan; Tao, Hao-Ran; Zhou, Fen-Fang; Zhang, Chi; Su, Fei; Wang, Shi-Pei; Liu, Qing; Xu, Li-Hua; Pan, Xue-Kai; Xie, Wei; Feng, Mao-Hui

    2017-06-01

    The sialyl Lewis X (SLe(x)) antigen encoded by the FUT7 gene is the ligand of endotheliam-selectin (E-selectin). The combination of SLe(x) antigen and E-selectin represents an important way for malignant tumor metastasis. In the present study, the effect of the SLe(x)-binding DNA aptamer on the adhesion and metastasis of hepatocellular carcinoma HepG2 cells in vitro was investigated. Reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence staining were conducted to detect the expression of FUT7 at both transcriptional and translational levels. The SLe(x) expression in HepG2 cells treated with different concentrations of SLe(x)-binding DNA aptamer was detected by flow cytometry. Besides, the adhesion, migration, and invasion of HepG2 cells were measured by cell adhesion assay, and the Transwell migration and invasion assay. The results showed that the FUT7 expression was up-regulated at both mRNA and protein levels in HepG2 cells. SLe(x)-binding DNA aptamer could significantly decrease the expression of SLe(x) in HepG2 cells. The cell adhesion assay revealed that the SLe(x)-binding DNA aptamer could effectively inhibit the interactions between E-selectin and SLe(x) in the HepG2 cells. Additionally, SLe(x)-binding DNA aptamers at 20 nmol/L were found to have the similar effect to the monoclonal antibody CSLEX-1. The Transwell migration and invasion assay revealed that the number of penetrating cells on the down-side of Transwell membrane was significantly less in cells treated with 5, 10, 20 nmol/L SLe(x)-binding DNA aptamer than those in the negative control group (PHepG2 cells, suggesting that the SLe(x)-binding DNA aptamer may be used as a potential molecular targeted drug against metastatic hepatocellular carcinoma.

  18. Fucoidan-induced ID-1 suppression inhibits the in vitro and in vivo invasion of hepatocellular carcinoma cells.

    Science.gov (United States)

    Cho, Yuri; Cho, Eun Ju; Lee, Jeong-Hoon; Yu, Su Jong; Kim, Yoon Jun; Kim, Chung Yong; Yoon, Jung-Hwan

    2016-10-01

    Hepatocellular carcinoma (HCC) is a fast growing tumor associated with a high tendency for vascular invasion and distant metastasis. Recently, we reported that fucoidan displays inhibitory effect on proliferation and invasion of HCC cells. In this study, we investigated the anti-metastatic effect of fucoidan on HCC cells and the key signal that modulates metastasis. The anti-metastatic effect of fucoidan was evaluated in vitro using an invasion assay with human HCC cells (Huh-7, SNU-761, and SNU-3085) under both normoxic (20% O2 and 5% CO2, at 37°C) and hypoxic (1% O2, 5% CO2, and 94% N2, at 37°C) conditions. Complementary DNA (cDNA) microarray analysis was performed to find the molecule which is significantly suppressed by fucoidan. In vivo study using a distant metastasis model by injecting SNU-761 cells into spleen via portal vein was performed to confirm the inhibitory effect by small interfering RNA (siRNA) transfection. Immunoblot analyses were used to investigate the signaling pathway. Fucoidan significantly suppressed the invasion of human HCC cells (Huh-7, SNU-761, and SNU-3085). Using cDNA microarray analysis, we found the molecule, ID-1, which was significantly suppressed by fucoidan treatment. Downregulation of ID-1 by siRNA significantly decreased invasion of HCC cells, both in vitro and in vivo (both Pfucoidan treatment. Moreover, the compensatory down-regulation of ID-1 against hypoxia-induced HCC invasion was observed. ID-1 is a novel therapeutic target for the treatment of metastatic HCC.

  19. MARVELD1 inhibited cell proliferation and enhance chemosensitivity via increasing expression of p53 and p16 in hepatocellular carcinoma.

    Science.gov (United States)

    Yu, Youtao; Zhang, Yubao; Hu, Jianran; Zhang, Hao; Wang, Shan; Han, Fang; Yue, Lei; Qu, Youpeng; Zhang, Yao; Liang, Hongjian; Nie, Huan; Li, Yu

    2012-04-01

    We have previously found that expression of MARVELD1 was remarkably downregulated in multiple tumor tissues, but unclear in hepatocellular carcinoma (HCC) and its function has not been explored yet. In the present study, to uncover the underlying mechanism of MARVELD1 in the pathogenesis and development of HCC, we investigated the expression pattern of MARVELD1 and its effect on tumor proliferation in HCC. The results indicated the frequent downregulation of MARVELD1 in clinic samples and cell lines of HCC resulted from promoter methylation, as well as genetic deletion. Furthermore, treatment of MARVELD1 unexpressing Hep3B2.1-7 and PLC/PRF/5 cells with the demethylating agent 5-aza-2' deoxycytidine restored its expression. Overexpression of MARVELD1 suppressed the proliferation of HCC cells in vitro and in vivo, whereas downregulation of endogenous MARVELD1 by shRNAs significantly enhanced these characters. MARVELD1 overexpression could enhance chemosensitivity of HCC cells to epirubicin and 10-hydroxycamptothecin. Corresponding to these results, the expression of p-ERK1/2 and cyclin D1 were decreased, whereas p16 and p53 were increased in MARVELD1-transfected cells. We also demonstrated that knockdown of MARVELD1 resulted in upregulation of p-ERK1/2 and cyclin D1, and downregulation of p16 and p53. Moreover, the effect of the decreased cell growth rate was significantly reversed when MARVELD1-overexpressing cells were trasfected with p53 or p16 siRNA. Our findings suggest that MARVELD1 is a tumor suppressor by negatively regulating proliferation, tumor growth and chemosensitivity of HCC cells via increasing p53 and p16 in vitro and in vivo. MARVELD1 may be a potential target for HCC therapy. © 2012 Japanese Cancer Association.

  20. LincRNA-p21 inhibits invasion and metastasis of hepatocellular carcinoma through miR-9/E-cadherin cascade signaling pathway molecular mechanism

    Directory of Open Access Journals (Sweden)

    Ding G

    2017-06-01

    Full Text Available Gangqiang Ding, Zhen Peng, Jia Shang, Yi Kang, Huibin Ning, Chongshan Mao Department of Infectious Diseases, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, China Abstract: In the previous study, it was found that long intergenic noncoding RNA-p21 (lincRNA-p21 was downregulated in hepatocellular carcinoma (HCC and lincRNA-p21 overexpression inhibited tumor invasion through inducing epithelial–mesenchymal transition. However, the underlying mechanism was not fully elaborated. In this study, lincRNA-p21 expression was measured in 12 paired HCC and nontumor adjacent normal tissues by ­quantitative real-time polymerase chain reaction. The effects of lincRNA-p21 on HCC cells were studied using lentivirus expressing lincRNA-p21 vector in vitro. The association between lincRNA-p21 level and miR-9 level was tested with the Spearman rank correlation. The effects of miR-9 on HCC cells were studied by using miR-9 inhibitor in vitro. Luciferase assay was used to validate the target of miR-9. The results showed that lincRNA-p21 was downregulated in human HCC tissues and cell lines. LincRNA-p21 overexpression significantly inhibited HCC cell migration and invasion in vitro. Besides, lincRNA-p21 negatively regulated miR-9 expression level, and miR-9 was upregulated in human HCC tissues and cells. MiR-9 knockdown inhibited HCC cell migration and invasion in vitro. Finally, the luciferase assay results showed that E-cadherin was a direct target of miR-9. The expression level of E-cadherin was found to be regulated by lincRNA-p21 and miR-9. Altogether, the results suggested that lincRNA-p21 inhibits migration and invasion of HCC cells through regulating miR-9-mediated E-cadherin cascade signaling pathway. Keywords: hepatocellular carcinoma, lincRNA-p21, miR-9, E-cadherin, epithelial–mesenchymal transition

  1. Phenolic phytochemicals derived from red pine (Pinus densiflora) inhibit the invasion and migration of SK-Hep-1 human hepatocellular carcinoma cells.

    Science.gov (United States)

    Lee, Sang Jun; Lee, Ki Won; Hur, Haeng Jeon; Chun, Ji Young; Kim, Seo Young; Lee, Hyong Joo

    2007-01-01

    Considerable attention has recently been focused on identifying chemopreventive phytochemicals derived from medicinal plants. Here, we analyzed phenolic phytochemicals from red pine (RP) leaves and found epigallocatechin gallate (EGCG) and epigallocatechin (EGC), and catechin gallate (CG) as their major phenolic phytochemicals. This article also investigated whether RP leaf extract and its phenolic phytochemicals inhibit the invasion of SK-Hep-1 human hepatocellular carcinoma cells (SK-Hep-1 cells). RP suppressed the invasion and the migration of SK-Hep-1 cells. EGCG and CG also inhibited the invasion and migration, with EGC exhibiting a lower efficacy. Matrix metalloproteinases (MMPs), particularly gelatinase-A (MMP-2) and gelatinase-B (MMP-9), degrade components of the basement membrane and are strongly implicated in invasion and metastasis formation of malignant tumors. RP suppressed both MMP-2 and MMP-9 activities. EGCG and CG reduced the activities of MMP-9 and MMP-2 in a dose-dependent manner, with EGC exhibiting a lower efficacy on both MMPs. Our results suggest that RP inhibits tumor invasion and migration, which may be attributed to the effects of EGCG and CG. In particular, EGCG plays a key role in the efficacy of RP against hepatocarcinogenesis.

  2. Synchronous Fibrolamellar Hepatocellular Carcinoma and Auricular Myxoma

    Directory of Open Access Journals (Sweden)

    Yessica M. González-Cantú

    2015-01-01

    Full Text Available Synchronic occurrence of benign and malignant tumors is extremely rare. Fibrolamellar hepatocellular carcinoma represents 1% to 2% of all hepatocarcinomas, while myxomas represent about half of all the cases of primary tumors of the heart. We present the case of a 53-year-old woman with a left atrial myxoma that was surgically removed. Several weeks later, the patient returned to the hospital with abdominal pain. CT scan showed a mass in the left lobe of the liver that was resected and diagnosed as fibrolamellar hepatocellular carcinoma. As of this writing, the patient is healthy.

  3. Synchronous Fibrolamellar Hepatocellular Carcinoma and Auricular Myxoma

    Science.gov (United States)

    González-Cantú, Yessica M.; Rodriguez-Padilla, Cristina; Tena-Suck, Martha Lilia; García de la Fuente, Alberto; Mejía-Bañuelos, Rosa María; Díaz Mendoza, Raymundo; Quintanilla-Garza, Samuel; Batisda-Acuña, Yolaester

    2015-01-01

    Synchronic occurrence of benign and malignant tumors is extremely rare. Fibrolamellar hepatocellular carcinoma represents 1% to 2% of all hepatocarcinomas, while myxomas represent about half of all the cases of primary tumors of the heart. We present the case of a 53-year-old woman with a left atrial myxoma that was surgically removed. Several weeks later, the patient returned to the hospital with abdominal pain. CT scan showed a mass in the left lobe of the liver that was resected and diagnosed as fibrolamellar hepatocellular carcinoma. As of this writing, the patient is healthy. PMID:26509093

  4. Hepatocellular carcinoma: epidemiology and risk factors

    Directory of Open Access Journals (Sweden)

    Kew MC

    2014-08-01

    Full Text Available Michael C Kew Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa Abstract: Hepatocellular carcinoma is one of the major malignant tumors in the world today. The number of new cases of the tumor increases year by year, and hepatocellular carcinoma almost always runs a fulminant course and carries an especially grave prognosis. It has a low resectability rate and a high recurrence rate after surgical intervention, and responds poorly to anticancer drugs and radiotherapy. Hepatocellular carcinoma does not have a uniform geographical distribution: rather, very high incidences occur in Eastern and Southeastern Asia and in sub-Saharan Black Africans. In these regions and populations, the tumor shows a distinct shift in age distribution toward the younger ages, seen to greatest extent in sub-Saharan Black Africans. In all populations, males are more commonly affected. The most common risk factors for hepatocellular carcinoma in resource-poor populations with a high incidence of the tumor are chronic hepatitis B virus infection and dietary exposure to the fungal hepatocarcinogen aflatoxin B1. These two causative agents act either singly or synergistically. Both the viral infection and exposure to the fungus occur from early childhood, and the tumor typically presents at an early age. Chronic hepatitis C virus infection is an important cause of hepatocellular carcinoma in resource-rich countries with a low incidence of the tumor. The infection is acquired in adulthood and hepatocellular carcinoma occurs later than it does with hepatitis B virus-induced tumors. In recent years, obesity and the metabolic syndrome have increased markedly in incidence and importance as a cause of hepatocellular carcinoma in some resource-rich regions. Chronic alcohol abuse remains an important risk factor for malignant transformation of hepatocytes, frequently in association with alcohol-induced cirrhosis. Excessive iron

  5. INVESTIGATION OF THE THERAPEUTIC EFFECT OF EXPRESSION OF TRAIL IN VIVO ON MOUSE HEPATOCELLULAR CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    张桂梅; 薛胜利; 张慧; 黎培员; 李东; 冯作化

    2003-01-01

    Objective: To construct an eukaryotic expressing plasmid of mouse TRAIL (mTRAIL), and investigate its ability to induce the apoptosis of hepatocellular carcinoma cells in vitro and in vivo, its inhibitory effect on the growth of hepatocellular carcinoma, and its synergism with pCH510, an eukaryotic expressing plasmid of recombinant human FN polypeptide. Methods: The eukaryotic expressing plasmid of mTRAIL was constructed by RT-PCR and DNA recombination techniques. Gene transfection was performed in vitro and in vivo. The apoptosis rate of hepatocellular carcinoma cells was measured by Flow Cytometry. The apoptosis of hepatocellular carcinoma cells was detected by TdT-mediated dUTP nick end labeling (TUNEL) and histochemistry techniques. The inhibitory effect of gene transfection on solid tumor was observed in mice. Results: The cDNA of mTRAIL was amplified by RT-PCR from the RNA of mouse spleen cells, and cloned into the eukaryotic expressing vector pcDNA3.1. The recombinant plasmid was designated as pX1. The BHK cells transfected with plasmid pX1 could attack H22 hepatocellular carcinoma cells and induce the apoptosis of them. The transfection of plasmid pX1 through injection into mouse muscles could inhibit the growth of hepatocellular carcinoma by inducing the apoptosis of tumor cells. Plasmid pX1 and pCH510 had a synergistic inhibitory effect on the hepatocellular carcinoma growth. Conclusion: Plamid pX1 could be expressed in cells and in vivo in mouse. The expression of pX1 in vivo and in vitro could induce the apoptosis of hepatocellular carcinoma cells and inhibit the growth of hepatocellular carcinoma. Plasmid pX1 and pCH510 had a synergistic inhibitory effect on the hepatocellular carcinoma growth.

  6. Primary prevention of hepatocellular carcinoma.

    Science.gov (United States)

    Yu, S Z

    1995-01-01

    Hepatocellular carcinoma (HCC) is one of the major cancers in China. Accordingly, the mortality rates in 1990 (per 100,000) were 20.10 in certain cities and 24.32 in certain counties. More than 90% of HCC cases and 70% of controls were infected with the hepatitis B virus (HBV) (Odds Ratio (OR) = 10-50). In the same group of patients, 8-27% of those with HCC and 0-11% of the healthy controls were also infected with hepatitis C (HCV) (OR = 2.11-17.29). There appears to be some correlation between HBV markers and the OR. The government requires that 85% of infants be immunized with HBV vaccine. In 1992, there were 3 million infants inoculated with HB vaccines. Aflatoxins have been found as contaminants in food, particularly in corn, peanut oil, soya sauce and fermented soya beans. The intake of aflatoxin B1 (AFB1) by people of ten different villages correlated with HCC mortality rates (r = 0.55; P aflatoxins. These adducts are higher in hyperendemic HCC areas and cases. Most people have now changed their staple food and eat rice instead of corn. Six large epidemiological studies have confirmed that people who drink pond-ditch water experience higher HCC mortality rates than people who drink deep-well water. Recent research has found that the blue-green algal toxin microcystin (MCYST) was a contaminant of pond-ditch water. MCYST is a strong promoter of HCC and will induce severe intrahepatic haemorrhages and liver necrosis. More than 80% of people in Qidong County have already changed their sources of water from pond-ditches to deep wells. Therefore, a combined strategy of the prevention of hepatitis, control of crops and control of drinking water is advocated for the primary prevention of HCC in China.

  7. Hepatocellular carcinoma: Therapy and prevention

    Institute of Scientific and Technical Information of China (English)

    Hubert E Blum

    2005-01-01

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The major etiologies and risk factors for the development of HCC are well defined and some of the multiple steps involved in hepatocarcinogenesis have been elucidated in recent years. Despite these scientific advances and the implementation of measures for the early detection of HCC in patients at risk, patient survival has not improved during the last three decades. This is due to the advanced stage of the disease at the time of clinical presentation and limited therapeutic options. The therapeutic options fall into five main categories: surgical interventions including tumor resection and liver transplantation, percutaneous interventions including ethanol injection and radiofrequency thermal ablation, transarterial interventions including embolization and chemoembolization, radiation therapy and drugs as well as gene and immune therapies. These therapeutic strategies have been evaluated in part in randomized controlled clinical trials that are the basis for therapeutic recommendations. Though surgery, percutaneous and transarterial interventions are effective in patients with limited disease (1-3 lesions, <5 cm in diameter) and compensated underlying liver disease (cirrhosis Child A), at the time of diagnosis more than 80% patients present with multicentric HCC and advanced liver disease or comorbidities that restrict the therapeutic measures to best supportive care. In order to reduce the morbidity and mortality of HCC, early diagnosis and the development of novel systemic therapies for advanced disease, including drugs, gene and immune therapies as well as primary HCC prevention are of paramount importance. Furthermore, secondary HCC prevention after successful therapeutic interventions needs to be improved in order to make an impact on the survival of patients with HCC. New technologies, including gene expression profiling and proteomic analyses, should allow to further

  8. New advances in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Sonia; Pascual; Iván; Herrera; Javier; Irurzun

    2016-01-01

    Hepatocellular carcinoma(HCC)is the leading cause of deaths in cirrhotic patients and the third cause of cancer related deaths.Most HCC are associated withwell known underlying risk factors,in fact,HCC arise in cirrhotic patients in up to 90%of cases,mainly due to chronic viral hepatitis and alcohol abuse.The worldwide prevention strategies are conducted to avoid the infection of new subjects and to minimize the risk of liver disease progression in infected patients.HCC is a condition which lends itself to surveillance as at-risk individuals can readily be identified.The American and European guidelines recommended implementation of surveillance programs with ultrasound every six months in patient atrisk for developing HCC.The diagnosis of HCC can be based on non-invasive criteria(only in cirrhotic patient)or pathology.Accurately staging patients is essential to oncology practice.The ideal tumour staging system in HCC needs to account for both tumour characteristics and liver function.Treatment allocation is based on several factors:Liver function,size and number of tumours,macrovascular invasion or extrahepatic spread.The recommendations in terms of selection for different treatment strategies must be based on evidence-based data.Resection,liver transplant and interventional radiology treatment are mainstays of HCC therapy and achieve the best outcomes in well-selected candidates.Chemoembolization is the most widely used treatment for unresectable HCC or progression after curative treatment.Finally,in patients with advanced HCC with preserved liver function,sorafenib is the only approved systemic drug that has demonstrated a survival benefit and is the standard of care in this group of patients.

  9. A rare case report: Carcinoma pancreas with hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Vikas Yadav

    2014-01-01

    Full Text Available Synchronous double malignancies involving different organs are relatively rare and uncommon finding. We report an interesting case of double malignancy in which a patient exhibited synchronous two separate carcinomas, pancreatic and hepatocellular carcinoma (HCC. Patient was a 64-year-old male who presented primarily with symptoms pertaining to the biliary obstruction and ultrasound of abdomen revealing pancreatic head mass. HCC was detected incidentally during the investigations for carcinoma pancreas.

  10. miR-502 inhibits cell proliferation and tumor growth in hepatocellular carcinoma through suppressing phosphoinositide 3-kinase catalytic subunit gamma

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Suling, E-mail: suling_chen86@163.com [Department of Infectious Disease, Heping Hospital Attached to Changzhi Medical College, Changzhi 046000 (China); Li, Fang; Chai, Haiyun; Tao, Xin [Department of Infectious Disease, Heping Hospital Attached to Changzhi Medical College, Changzhi 046000 (China); Wang, Haili [Department of Hematology, Heping Hospital Attached to Changzhi Medical College, Changzhi 046000 (China); Ji, Aifang [Central Laboratory, Heping Hospital Attached to Changzhi Medical College, Changzhi 046000 (China)

    2015-08-21

    MicroRNAs (miRNAs) play a key role in carcinogenesis and tumor progression in hepatocellular carcinoma (HCC). In the present study, we demonstrated that miR-502 significantly inhibits HCC cell proliferation in vitro and tumor growth in vivo. G1/S cell cycle arrest and apoptosis of HCC cells were induced by miR-502. Phosphoinositide 3-kinase catalytic subunit gamma (PIK3CG) was identified as a direct downstream target of miR-502 in HCC cells. Notably, overexpression of PIK3CG reversed the inhibitory effects of miR-502 in HCC cells. Our findings suggest that miR-502 functions as a tumor suppressor in HCC via inhibition of PI3KCG, supporting its utility as a promising therapeutic gene target for this tumor type. - Highlights: • miR-502 suppresses HCC cell proliferation in vitro and tumorigenicity in vivo. • miR-502 regulates cell cycle and apoptosis in HCC cells. • PIK3CG is a direct target of miR-502. • miR-502 and PIK3CG expression patterns are inversely correlated in HCC tissues.

  11. Fucoidan Elevates MicroRNA-29b to Regulate DNMT3B-MTSS1 Axis and Inhibit EMT in Human Hepatocellular Carcinoma Cells.

    Science.gov (United States)

    Yan, Ming-De; Yao, Chih-Jung; Chow, Jyh-Ming; Chang, Chia-Lun; Hwang, Pai-An; Chuang, Shuang-En; Whang-Peng, Jacqueline; Lai, Gi-Ming

    2015-09-24

    Accumulating evidence has revealed that fucoidan exhibits anti-tumor activities by arresting cell cycle and inducing apoptosis in many types of cancer cells including hepatocellular carcinoma (HCC). Exploring its effect on microRNA expression, we found that fucoidan markedly upregulated miR-29b of human HCC cells. The induction of miR-29b was accompanied with suppression of its downstream target DNMT3B in a dose-dependent manner. The reduction of luciferase activity of DNMT3B 3'-UTR reporter by fucoidan was as markedly as that by miR-29b mimic, indicating that fucoidan induced miR-29b to suppress DNMT3B. Accordingly, the mRNA and protein levels of MTSS1 (metastasis suppressor 1), a target silenced by DNMT3B, were increased after fucoidan treatment. Furthermore, fucoidan also down-regulated TGF-β receptor and Smad signaling of HCC cells. All these effects leaded to the inhibition of EMT (increased E-cadherin and decreased N-cadherin) and prevention of extracellular matrix degradation (increased TIMP-1 and decreased MMP2, 9), by which the invasion activity of HCC cells was diminished. Our results demonstrate the profound effect of fucoidan not only on the regulation of miR-29b-DNMT3B-MTSS1 axis but also on the inhibition of TGF-β signaling in HCC cells, suggesting the potential of using fucoidan as integrative therapeutics against invasion and metastasis of HCC.

  12. Solamargine inhibits migration and invasion of human hepatocellular carcinoma cells through down-regulation of matrix metalloproteinases 2 and 9 expression and activity.

    Science.gov (United States)

    Sani, Iman Karimi; Marashi, Seyed Hassan; Kalalinia, Fatemeh

    2015-08-01

    Solamargine is a steroidal alkaloid glycoside isolated from Solanum nigrum. The aim of this study was to investigate the effects of solamargine on tumor migration and invasion in aggressive human hepatocellular carcinoma cells. The MTT assay was used to assess the effects of solamargine on the viability of HepG2 cells. Migration and invasion ability of HepG2 cells under solamargine treatment were examined by a wound healing migration assay and Boyden chamber assay, respectively. Western blotting assays were used to detect the expression of MMP-2 and MMP-9 proteins and MMP-2 and MMP-9 activity were analyzed by gelatin zymography assay. Solamargine reduced HepG2 cell viability in a concentration-dependent manner. At 7.5μM solamargine decreased cell viability by less than 20% in HepG2 cells. A wound healing migration assay and Boyden chamber invasion assay showed that solamargine significantly inhibited in vitro migration and invasion of HepG2 cells. At the highest dose, solamargine decreased cell migration and invasion by more than 70% and 72% in HepG2 cells, respectively. Western blotting and gelatin zymography results showed that solamargine reduced expression and function of MMP-2 and MMP-9 proteins. In conclusion, the results showed that solamargine significantly inhibits migration and invasion of HepG2 cells by down-regulating MMP-2 and MMP-9 expression and activity.

  13. Salinomycin decreases doxorubicin resistance in hepatocellular carcinoma cells by inhibiting the β-catenin/TCF complex association via FOXO3a activation

    Science.gov (United States)

    Chen, Wei; Zhi, Xiao; Feng, Xinhua; Bai, Xueli; Liang, Tingbo

    2015-01-01

    Doxorubicin is a conventional and effective chemotherapy drug against hepatocellular carcinoma (HCC). However, during long-term doxorubicin monotherapy, HCC cells may eventually develop acquired-resistance to doxorubicin which results in recurrence and a poor prognosis. Salinomycin, an ionophore antibiotic, was recently reported to selectively kill human cancer stem cells (CSCs) which were response for chemoresistance. In this study, salinomycin was found to exert synergistic cytotoxicity with doxorubicin in HCC cells and be capable of inhibiting doxorubicin-induced epithelial-mesenchymal transition (EMT), an important cellular process involved in the acquired chemoresistance of tumors. Further experiments revealed that FOXO3a, a multifunctional transcription factor that can be activated by salinomycin, was vital in mediating doxorubicin-induced EMT. In addition, activated FOXO3a disturbed the interaction between β-catenin and TCF and inhibited the expression of β-catenin/TCF target genes (ZEB1, c-Myc and CyclinD1), which played important roles in doxorubicin-induced EMT in HCC cells. Finally, the enhanced curative efficacy of combination treatment of doxorubicin and salinomycin for HCC was confirmed in established xenograft models. In summary, the present study identifies a new doxorubicin-based chemotherapy for advanced HCC and provides a potential anti-cancer strategy targeting FOXO3a and related cell pathway molecules. PMID:25871400

  14. Bmi1 gene silencing inhibits the proliferation and invasiveness of human hepatocellular carcinoma cells and increases their sensitivity to 5-fluorouracil.

    Science.gov (United States)

    Zhang, Rui; Xu, Lei-Bo; Yue, Xiu-Jing; Yu, Xian-Huan; Wang, Jie; Liu, Chao

    2013-03-01

    The Bmi1 gene has been reported to play important roles in cancer initiation and progression. The aim of this study was to investigate the effects of RNA interference (RNAi)-mediated silencing of Bmi1 gene expression on the proliferation and invasiveness of hepatocellular carcinoma (HCC) cells and on the efficacy of chemotherapy in HCC patients. The Bmi1 gene was silenced by Bmi1-siRNA (small interfering RNA) in the human HCC cell lines HepG2 and Bel-7402, and the gene expression levels were assayed by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting. The proliferation and migration of Bmi1-silenced tumor cells and their sensitivity to 5-FU treatment were determined by Cell Counting Kit-8 (CCK-8), transwell assays and 4',6-diamidino-2-phenylindole (DAPI) staining and flow cytometry, respectively. Bmi1-siRNA inhibited the Bmi1 expression at both the mRNA and protein levels in HCC cells. Proliferation and migration of HCC cells treated with Bmi1-siRNA was significantly lower compared to that of the control cells. Moreover, Bmi1 gene silencing increased the percentage of apoptotic cells treated by 5-FU and decreased the IC50 values of 5-FU to a greater extent. Downregulation of the Bmi1 gene by RNAi can inhibit the proliferation and invasivesness of HCC cells and increase their sensitivity to 5-FU treatment.

  15. Salinomycin decreases doxorubicin resistance in hepatocellular carcinoma cells by inhibiting the β-catenin/TCF complex association via FOXO3a activation.

    Science.gov (United States)

    Zhou, Yue; Liang, Chao; Xue, Fei; Chen, Wei; Zhi, Xiao; Feng, Xinhua; Bai, Xueli; Liang, Tingbo

    2015-04-30

    Doxorubicin is a conventional and effective chemotherapy drug against hepatocellular carcinoma (HCC). However, during long-term doxorubicin monotherapy, HCC cells may eventually develop acquired-resistance to doxorubicin which results in recurrence and a poor prognosis. Salinomycin, an ionophore antibiotic, was recently reported to selectively kill human cancer stem cells (CSCs) which were response for chemoresistance. In this study, salinomycin was found to exert synergistic cytotoxicity with doxorubicin in HCC cells and be capable of inhibiting doxorubicin-induced epithelial-mesenchymal transition (EMT), an important cellular process involved in the acquired chemoresistance of tumors. Further experiments revealed that FOXO3a, a multifunctional transcription factor that can be activated by salinomycin, was vital in mediating doxorubicin-induced EMT. In addition, activated FOXO3a disturbed the interaction between β-catenin and TCF and inhibited the expression of β-catenin/TCF target genes (ZEB1, c-Myc and CyclinD1), which played important roles in doxorubicin-induced EMT in HCC cells. Finally, the enhanced curative efficacy of combination treatment of doxorubicin and salinomycin for HCC was confirmed in established xenograft models. In summary, the present study identifies a new doxorubicin-based chemotherapy for advanced HCC and provides a potential anti-cancer strategy targeting FOXO3a and related cell pathway molecules.

  16. Inhibition of MEK/ERK activation attenuates autophagy and potentiates pemetrexed-induced activity against HepG2 hepatocellular carcinoma cells.

    Science.gov (United States)

    Tong, Yongxi; Huang, Haijun; Pan, Hongying

    2015-01-02

    Identification of efficient chemo-therapeutic/chemo-preventive agents for treatment of hepatocellular carcinoma (HCC) is important. In this study, we examined the activity of pemetrexed, an anti-folate chemotherapy drug, against HepG2 human HCC cells. Pemetrexed treatment in vitro exerted weak but significant cytotoxic activity against HepG2 cells. When analyzing the possible pemetrexed-resistance factors, we indentified that pemetrexed treatment in HepG2 cells induced cyto-protective autophagy activation, evidenced by GFP-light chain 3B (LC3B) puncta formation, p62 downregulation and Beclin-1/LC3B-II upregulation. Correspondingly, autophagy inhibitors, including bafliomycin A1, 3-methyladenine and chloroquine, enhanced pemetrexed-induced cytotoxicity against HepG2 cells. Further, RNAi-mediated knockdown of Beclin-1 in HepG2 cells also increased pemetrexed sensitivity. Pemetrexed activated MEK (mitogen-activated protein kinase/ERK kinase)/ERK (extracellular-signal-regulated kinase) signaling in HepG2 cells, which was required for autophagy induction. Pharmacological inhibition of MEK/ERK activation attenuated pemetrexed-induced autophagy, enhanced HepG2 cell death and apoptosis. In summary, pemetrexed activates MEK/ERK-dependent cyto-protective autophagy, and inhibition of this pathway potentiates pemetrexed's activity in HepG2 cells. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Hepatocellular carcinoma: risk groups, surveillance and outcome

    NARCIS (Netherlands)

    van Meer, S

    2016-01-01

    The burden of hepatocellular carcinoma (HCC) has changed in the past few decades. Although the majority of HCC cases develops in East Asia and Sub-Saharan Africa, HCC has become an increasing problem in Western countries such as the Netherlands. Surveillance for HCC is controversial because of limit

  18. Hepatocellular carcinoma: risk groups, surveillance and outcome

    NARCIS (Netherlands)

    van Meer, S

    2016-01-01

    The burden of hepatocellular carcinoma (HCC) has changed in the past few decades. Although the majority of HCC cases develops in East Asia and Sub-Saharan Africa, HCC has become an increasing problem in Western countries such as the Netherlands. Surveillance for HCC is controversial because of

  19. Liver transplantation in patients with hepatocellular carcinoma

    NARCIS (Netherlands)

    Polak, Wojciech G.; Soyama, Akihiko; Slooff, Maarten J. H.

    2008-01-01

    Liver transplantation has a definitive place in the treatment of patients with hepatocellular carcinoma (HCC) in a cirrhotic liver. Patients with a tumor load within the Milan criteria have excellent survival comparable to survival in patients with benign indications. When tumor load exceeds the Mil

  20. Radioembolisation for treatment of pediatric hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Hawkins, Clifford Matthew; Kukreja, Kamlesh [Cincinnati Children' s Hospital Medical Center, Department of Radiology, Cincinnati, OH (United States); Geller, James I. [Cincinnati Children' s Hospital Medical Center, Department of Hematology/Oncology, Cincinnati, OH (United States); Schatzman, Carmen; Ristagno, Ross [University of Cincinnati, UC Health, Department of Radiology, Division of Interventional Radiology, Cincinnati, OH (United States)

    2013-07-15

    Transarterial radioembolisation with yttrium-90 (TARE-Y90), a catheter-directed therapy, has been used extensively in adults to treat primary and secondary hepatic malignancies. To our knowledge, the use of this palliative technique has not been described in children. We present two children with unresectable hepatocellular carcinoma (HCC) treated with TARE-Y90. (orig.)

  1. Ursolic acid inhibited growth of hepatocellular carcinoma HepG2 cells through AMPKα-mediated reduction of DNA methyltransferase 1.

    Science.gov (United States)

    Yie, Yinyi; Zhao, Shunyu; Tang, Qin; Zheng, Fang; Wu, Jingjing; Yang, LiJuan; Deng, ShiGuan; Hann, Swei Sunny

    2015-04-01

    Hepatocellular carcinoma (HCC), the major histological subtype of primary liver cancer, remains one of the most common malignancies worldwide. Due to the complicated pathogenesis of this malignancy, the outcome for comprehensive treatment is limited. Chinese herbal medicine (CHM) is emerging as a promising choice for its multi-targets and coordinated intervention effects against HCC. Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid found in CHM, exerts anti-tumor effects and is emerging as an effective compound for cancer prevention and therapy. However, the molecular mechanisms underlying the action of UA remain largely unknown. In this study, we showed that UA inhibited the growth of HCC cells and induced apoptosis in the dose- and time-dependent fashion. Furthermore, we found that UA induced phosphorylation of AMP-activated protein kinase alpha (AMPKα) and suppressed the protein expression of DNA methyltransferase 1 (DNMT1) in the dose-dependent manner. The inhibitor of AMPK, compound C blocked, while an activator of AMPK, metformin augmented the effect of UA on DNMT1 expression. In addition, UA suppressed the expression of transcription factor Sp1. Conversely, overexpression of Sp1 reversed the effect of UA on DNMT1 expression and cell growth. Collectively, our results show for the first time that UA inhibits growth of HCC through AMPKα-mediated inhibition of Sp1; this in turn results in inhibition of DNMT1. This study reveals a potential novel mechanism by which UA controls growth of HCC cells and suggests that DNMT1 could be novel target for HCC chemoprevention and treatment.

  2. 1810011o10 Rik Inhibits the Antitumor Effect of Intratumoral CD8+ T Cells through Suppression of Notch2 Pathway in a Murine Hepatocellular Carcinoma Model

    Science.gov (United States)

    Dai, Kai; Huang, Ling; Huang, Ya-bing; Chen, Zu-bing; Yang, Li-hua; Jiang, Ying-an

    2017-01-01

    The mechanisms by which tumor-responsive CD8+ T cells are regulated are important for understanding the tumor immunity and for developing new therapeutic strategies. In current study, we identified the expression of 1810011o10 Rik, which is the homolog of human thyroid cancer 1, in intratumoral activated CD8+ T cells in a murine hepatocellular carcinoma (HCC) implantation model. To investigate the role of 1810011o10 Rik in the regulation of antitumor activity of CD8+ T cells, normal CD8+ T cells were transduced with 1810011o10 Rik-expressing lentiviruses. Although 1810011o10 Rik overexpression did not influence agonistic antibody-induced CD8+ T cell activation in vitro, it inhibited the cytotoxic efficacy of CD8+ T cells on HCC cells in vivo. 1810011o10 Rik overexpression impeded CD8+ T cell-mediated HCC cell apoptosis and favored tumor cell growth in vivo. Further investigation revealed that 1810011o10 Rik blocked the nuclear translocation of Notch2 intracellular domain, which is crucial for CD8+ T cell activity. Furthermore, a brief in vitro experiment suggested that both antigen-presenting cells and TGF-β might be necessary for the upregulation of Rik expression in activated CD8+ T cells. In general, our study disclosed a novel mechanism underlying the negative regulation of antitumor CD8+ T cells during HCC progression.

  3. CKLF-Like MARVEL Transmembrane Domain-Containing Member 3 (CMTM3) Inhibits the Proliferation and Tumorigenisis in Hepatocellular Carcinoma Cells.

    Science.gov (United States)

    Li, Wujun; Zhang, Shaobo

    2017-01-26

    The CKLF-like MARVEL transmembrane domain-containing 3 (CMTM3), a member of the CMTM family, was found in several human tumors and plays an important role in the development and progression of tumors. However, the role of CMTM3 in hepatocellular carcinoma (HCC) remains largely unknown. Thus, in the present study, we explored its expression pattern in human HCC cell lines, as well as its functions in HCC cells. Our results demonstrated that the expression of CMTM3 is lowly expressed in HCC cell lines. In vitro, we found that overexpression of CMTM3 obviously inhibited the proliferation, invasion, and EMT process in HCC cells. Furthermore, overexpression of CMTM3 significantly downregulated the expression levels of phosphorylation of JAK2 and STAT3 in HepG2 cells. In vivo, overexpression of CMTM3 attenuated the tumor growth in Balb/c nude mice. In conclusion, we demonstrated that CMTM3 could play an important role in HCC metastasis by EMT induction via, at least partially, suppressing the JAK2/STAT3 signaling pathway. Therefore, CMTM3 may serve as a potential molecular target in the prevention and/or treatment of HCC invasion and metastasis.

  4. File list: DNS.Liv.05.AllAg.Carcinoma,_Hepatocellular [Chip-atlas[Archive

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  19. File list: His.Liv.50.AllAg.Carcinoma,_Hepatocellular [Chip-atlas[Archive

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  20. A novel mechanism of hepatocellular carcinoma cell apoptosis induced by lupeol via Brain-Derived Neurotrophic Factor Inhibition and Glycogen Synthase Kinase 3 beta reactivation.

    Science.gov (United States)

    Zhang, Lingli; Tu, Yi; He, Wen; Peng, Yan; Qiu, Zhenpeng

    2015-09-05

    Lupeol is a naturally available triterpenoid with selective anticancerous potential on various human cancer cells. The present study shows that lupeol can inhibit cell proliferation of hepatocellular carcinoma (HCC) HCCLM3 cells in a time- and dose-dependent manner, through caspase-3 dependent activation and Poly ADP-Ribose Polymerase (PARP) cleavage. Lupeol-induced cell death is associated with a marked decrease in the protein expression of Brain-Derived Neurotrophic Factor (BDNF) and ser-9-phosphoryltion of Glycogen Synthase Kinase 3 Beta (GSK-3β), with concomitant suppression of Akt1, phosphatidyl inositol 3-kinase (PI3K), β-catenin, c-Myc and Cyclin D1 mRNA expression. Suppressing overexpression of BDNF by lupeol results in decreased protein expression of p-Akt and PI3K (p110α), as well as reactivation of GSK-3β function in HepG2 cells. Lupeol treatment also inhibits LiCl-induced activation of Wnt signaling pathway and exerts the in vitro anti-invasive activity in Huh-7 cells. LiCl-triggered high expression of β-catenin, c-Myc and Cyclin D1 protein is reduced followed by lupeol exposure. The findings suggest a mechanistic link between caspase dependent pathway, BDNF secretion and Akt/PI3K/GSK-3β in HCC cells. These results indicate that lupeol can suppress HCC cell proliferation by inhibiting BDNF secretion and phosphorylation of GSK-3β(Ser-9), cooperated with blockade of Akt/PI3K and Wnt signaling pathway.

  1. The EGFR/ErbB3 Pathway Acts as a Compensatory Survival Mechanism upon c-Met Inhibition in Human c-Met+ Hepatocellular Carcinoma.

    Directory of Open Access Journals (Sweden)

    Steven N Steinway

    Full Text Available c-Met, a high-affinity receptor for Hepatocyte Growth Factor (HGF, plays a critical role in tumor growth, invasion, and metastasis. Hepatocellular carcinoma (HCC patients with activated HGF/c-Met signaling have a significantly worse prognosis. Targeted therapies using c-Met tyrosine kinase inhibitors are currently in clinical trials for HCC, although receptor tyrosine kinase inhibition in other cancers has demonstrated early success. Unfortunately, therapeutic effect is frequently not durable due to acquired resistance.We utilized the human MHCC97-H c-Met positive (c-Met+ HCC cell line to explore the compensatory survival mechanisms that are acquired after c-Met inhibition. MHCC97-H cells with stable c-Met knockdown (MHCC97-H c-Met KD cells were generated using a c-Met shRNA vector with puromycin selection and stably transfected scrambled shRNA as a control. Gene expression profiling was conducted, and protein expression was analyzed to characterize MHCC97-H cells after blockade of the c-Met oncogene. A high-throughput siRNA screen was performed to find putative compensatory survival proteins, which could drive HCC growth in the absence of c-Met. Findings from this screen were validated through subsequent analyses.We have previously demonstrated that treatment of MHCC97-H cells with a c-Met inhibitor, PHA665752, results in stasis of tumor growth in vivo. MHCC97-H c-Met KD cells demonstrate slower growth kinetics, similar to c-Met inhibitor treated tumors. Using gene expression profiling and siRNA screening against 873 kinases and phosphatases, we identified ErbB3 and TGF-α as compensatory survival factors that are upregulated after c-Met inhibition. Suppressing these factors in c-Met KD MHCC97-H cells suppresses tumor growth in vitro. In addition, we found that the PI3K/Akt signaling pathway serves as a negative feedback signal responsible for the ErbB3 upregulation after c-Met inhibition. Furthermore, in vitro studies demonstrate that

  2. Astaxanthin Inhibits Proliferation and Induces Apoptosis of Human Hepatocellular Carcinoma Cells via Inhibition of Nf-Κb P65 and Wnt/Β-Catenin in Vitro

    Directory of Open Access Journals (Sweden)

    Jingjing Li

    2015-09-01

    Full Text Available Hepatocellular carcinoma (HCC is a malignant tumor that can cause systemic invasion; however, the exact etiology and molecular mechanism are unknown. Astaxanthin (ASX, a powerful antioxidant, has efficient anti-oxidant, anti-inflammatory, and other activities, and has great research prospects in cancer therapy. We selected the human hepatoma cell lines, LM3 and SMMC-7721, to study the anti-tumor effect and related mechanisms of ASX. The cell lines were treated with different concentrations of ASX, and its solvent DMSO as a control, for different time periods and the results were determined using CCK8, qRT-PCR, WB, apoptotic staining, and flow cytometry. ASX induced significant apoptosis of HCC cells, and its effect may have been caused by NF-κB p65 and Wnt/β-catenin down-regulation via negative activation of PI3K/Akt and ERK. Antitumor research on ASX has provided us with a potential therapy for patients with hepatomas.

  3. Nano-pulse stimulation (NPS) ablate tumors and inhibit lung metastasis on both canine spontaneous osteosarcoma and murine transplanted hepatocellular carcinoma with high metastatic potential

    OpenAIRE

    Chen, Xinhua; Chen, Yiling; Jiang, Jianwen; Wu, Liming; Yin, Shengyong; Miao, Xudong; Swanson, Robert J.; Zheng, Shusen

    2017-01-01

    Background Nanosecond pulsed electric field (nsPEF), which is also termed as nano-pulse stimulation (NPS), has the potential of stimulating immune responses toward cancer cells. The current study investigates its local and systemic antitumor efficacy in vivo in late stage tumors with lung metastasis. Method The 12 canines with spontaneous osteosarcomas and 12 nude mice transplanted with human hepatocellular carcinoma were divided randomly and were given NPS treatment, surgery or no treatment ...

  4. miR-29c targets TNFAIP3, inhibits cell proliferation and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Chun-Mei [Department of Microbiology, Shandong University School of Medicine, Jinan 250012 (China); Department of Pathophysiology, Shandong University School of Medicine, Jinan 250012 (China); Wang, Yan; Fan, Chun-Guang; Xu, Fei-Fei [Department of Pathophysiology, Shandong University School of Medicine, Jinan 250012 (China); Sun, Wen-Sheng [Institute of Immunology, Shandong University School of Medicine, Jinan 250012 (China); Liu, Yu-Gang, E-mail: liu.yugang@sdu.edu.cn [Department of Pathophysiology, Shandong University School of Medicine, Jinan 250012 (China); Jia, Ji-Hui, E-mail: jiajihui@sdu.edu.cn [Department of Microbiology, Shandong University School of Medicine, Jinan 250012 (China)

    2011-08-05

    Highlights: {yields} miR-29c was significantly downregulated in HBV-related HCC. {yields} TNFAIP3 was found to be inversely correlated with miR-29c levels and identified as a target of miR-29c. {yields} Overexpression of miR-29c suppressed TNFAIP3. {yields} miR-29c inhibited HBV DNA replication, cell proliferation and induced apoptosis. -- Abstract: Recent studies have revealed that microRNA-29c (miR-29c) is involved in a variety of biological processes including carcinogenesis. Here, we report that miR-29c was significantly downregulated in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) cell lines as well as in clinical tissues compared with their corresponding controls. Tumor necrosis factor alpha-induced protein 3 (TNFAIP3), a key regulator in inflammation and immunity, was found to be inversely correlated with miR-29c levels and was identified as a target of miR-29c. Overexpression of miR-29c in HepG2.2.15 cells effectively suppressed TNFAIP3 expression and HBV DNA replication as well as inhibited cell proliferation and induced apoptosis. We conclude that miR-29c may play an important role as a tumor suppressive microRNA in the development and progression of HBV-related HCC by targeting TNFAIP3. Thus miR-29c and TNFAIP3 represent key diagnostic markers and potential therapeutic targets for the prevention and treatment of HBV infection.

  5. Fucoidan Elevates MicroRNA-29b to Regulate DNMT3B-MTSS1 Axis and Inhibit EMT in Human Hepatocellular Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Ming-De Yan

    2015-09-01

    Full Text Available Accumulating evidence has revealed that fucoidan exhibits anti-tumor activities by arresting cell cycle and inducing apoptosis in many types of cancer cells including hepatocellular carcinoma (HCC. Exploring its effect on microRNA expression, we found that fucoidan markedly upregulated miR-29b of human HCC cells. The induction of miR-29b was accompanied with suppression of its downstream target DNMT3B in a dose-dependent manner. The reduction of luciferase activity of DNMT3B 3′-UTR reporter by fucoidan was as markedly as that by miR-29b mimic, indicating that fucoidan induced miR-29b to suppress DNMT3B. Accordingly, the mRNA and protein levels of MTSS1 (metastasis suppressor 1, a target silenced by DNMT3B, were increased after fucoidan treatment. Furthermore, fucoidan also down-regulated TGF-β receptor and Smad signaling of HCC cells. All these effects leaded to the inhibition of EMT (increased E-cadherin and decreased N-cadherin and prevention of extracellular matrix degradation (increased TIMP-1 and decreased MMP2, 9, by which the invasion activity of HCC cells was diminished. Our results demonstrate the profound effect of fucoidan not only on the regulation of miR-29b-DNMT3B-MTSS1 axis but also on the inhibition of TGF-β signaling in HCC cells, suggesting the potential of using fucoidan as integrative therapeutics against invasion and metastasis of HCC.

  6. miR-187-3p inhibits the metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting S100A4.

    Science.gov (United States)

    Dou, Changwei; Liu, Zhikui; Xu, Meng; Jia, Yuli; Wang, Yufeng; Li, Qing; Yang, Wei; Zheng, Xin; Tu, Kangsheng; Liu, Qingguang

    2016-10-28

    miR-187-3p, a novel cancer-related microRNA, was previously reported to play promoting or suppressive roles in different malignancies. However, the expression level, biological function, and underlying mechanisms of miR-187-3p in hepatocellular carcinoma (HCC) remain unknown. This study demonstrated that miR-187-3p was significantly down-regulated in HCC tissues and cell lines, and was associated with advanced TNM stage and metastasis in HCC. Functional studies confirmed that miR-187-3p could inhibit the metastasis of HCC both in vitro and in vivo. Moreover, we proved that miR-187-3p could prevent the epithelial-mesenchymal transition (EMT) of HCC cells. Mechanically, S100A4 was a direct downstream target of miR-187-3p, and mediated the functional influence of miR-187-3p in HCC. Furthermore, miR-187-3p and S100A4 expression was evidently correlated with adverse clinical features and poor prognosis of HCC. Lastly, we showed that hypoxia was responsible for the significantly decreased level of miR-187-3p in HCC, and miR-187-3p was involved in the promoting effects of hypoxia on the metastasis and EMT of HCC cells. Taken together, miR-187-3p inhibits the metastasis and EMT in HCC by targeting S100A4. miR-187-3p can serve as a prognostic indicator and a promising therapeutic target for HCC patients.

  7. Radiotherapy for metastatic fibrolamellar hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Justin G. Peacock

    2013-07-01

    Full Text Available Fibrolamellar hepatocellular carcinoma (FLHCC is a rare variant of hepatocellular carcinoma (HCC that commonly affects young individuals without a prior history of liver disease. FLHCC commonly results in a better prognosis than HCC; however, the risk of recurrence and metastatic disease is high. FLHCC is typically treated by primary resection of the tumor with 50-75% cure rates. The use of radiation therapy in FLHCC has not been assessed on its own, and may show some success in a very few reported combination therapy cases. We report on the successful use of radiation therapy in a case of metastatic FLHCC to the lung following primary and secondary resections. Our treatment of the large, metastatic, pulmonary FLHCC tumor with 40 Gy in 10 fractions resulted in an 85.9% tumor volume decrease over six months. This suggests FLHCC may be a radiosensitive tumor and radiotherapy may be valuable in unresectable or metastatic tumors.

  8. Treatment of hepatocellular carcinoma: present and future.

    Science.gov (United States)

    Genco, Chiara; Cabibbo, Giuseppe; Maida, Marcello; Brancatelli, Giuseppe; Galia, Massimo; Alessi, Nicola; Butera, Giuseppe; Genova, Claudio; Romano, Piero; Raineri, Maurizio; Giarratano, Antonello; Midiri, Massimo; Cammà, Calogero

    2013-04-01

    Hepatocellular carcinoma is a major health problem. It is the sixth most common cancer worldwide and the third most common cause of cancer-related death. Despite the availability of several treatment opportunities, diagnosis is still made in an advanced phase, limiting application of most therapeutic choices that currently are based on the Barcelona Clinic Cancer Liver Classification and include surgical resection, orthotopic liver transplantation and ablative methods for very early and early disease, arterial chemoembolization for intermediate stages and systemic therapy with sorafenib for advanced hepatocellular carcinoma. Thanks to novel advancements in knowledge of molecular pathogenesis of this tumor, many new systemic agents and locoregional treatments are in different stages of clinical development and they represent an important promise of further improvements in patients' survival.

  9. Epidemiology of hepatocellular carcinoma (HCC) in hemophilia.

    Science.gov (United States)

    Shetty, Shrimati; Sharma, Nitika; Ghosh, Kanjaksha

    2016-03-01

    Hepatocellular carcinoma (HCC) is an important cause of increasing mortality in elderly hemophilia population. Majority of the patients treated with virus non-inactivated factor concentrates prepared from large plasma pools prior to 1985 have been found to be infected with hepatitis C virus (HCV), a major risk factor for HCC. A PubMed search of articles published until February 2015 was performed utilizing the keywords hemophilia, malignancy, neoplasm, cancer, mortality, ageing hemophilia, epidemiology, hepatocellular carcinoma and liver cancer and the relevant articles were included. Contradictory reports are available in literature on the incidence of cancers in general in hemophilia population. Almost all the studies where the incidence of HCC or mortality due to HCC have been analyzed in hemophilia population show that a vast majority of these patients are HCV infected. The incidence of HCC though higher in hemophilic population is related to the higher incidence of HCV infection and not due to the hemophilia phenotype.

  10. Hepatocellular carcinoma in the Malaysian Orang Asli.

    Science.gov (United States)

    Sumithran, E; Prathap, K

    1976-05-01

    Necropsies were performed on 285 consecutively unclaimed Orang Asli bodies from Gombak Orang Asli Hospital during an eight-year period from May 1967 to April 1975. Of the 25 malignant neoplasms, hepatocellular carcinoma was by far the commonest (36%). The nine patients with this neoplasm had coexistant macronodular cirrhosis. There were 20 cases of cirrhosis; 45% of these had coexistant hepatocellular carcinoma. The 53,000 Orang Aslis living in West Malaysia comprise three tribes, the Negrito, Senoi, and Melayu Asli (Proto Malays). The Sinoi appear to have a high predilection for liver cancer, all our nine cases occurring in this group. These aboriginal people live in the jungles where they practice shifting cultivation and maintain their own dietary and social customs. Detailed studies of their dietary habits may provide a clue to the etiology of liver cancer in these people.

  11. Current management strategy of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Bernardino Rampone; Beniamino Schiavone; Antonio Martino; Carmine Viviano; Giuseppe Confuorto

    2009-01-01

    Hepatocellular carcinoma (HCC) still remains a considerable challenge for surgeons. Surgery, including liver transplantation, is the most important therapeutic approach for patients with this disease. HCC is frequently diagnosed at advanced stages and has a poor prognosis with a high mortality rate even when surgical resection has been considered potentially curative. This brief report summarizes the current status of the management of this malignancy and includes a short description of new pharmacological approaches in HCC treatment.

  12. Fibrolamellar Hepatocellular Carcinoma: A Case Report

    Directory of Open Access Journals (Sweden)

    "N. Ebrahimi Daryani

    2005-08-01

    Full Text Available Introduction & Background: Fibrolamellar hepatocel-lular carcinoma occurs in non-cirrhotic livers, most frequently in the adolescents or young adults without sex predominance, and the prognosis is more favor-able than that of the usual hepatocellular carcinoma. It is a rare condition; accounting for less than 1% of primary liver cancers. Case Presentation: This is a seventeen-year old male patient with history of right upper quadrant abdomi-nal pain, with no hepatomegaly. Liver function tests and serological markers for viral B, C hepatitis and tumor markers were normal. CT scan demonstrated a massive hyper- vascular lesion in the liver and the histological examination was reported as a typical fibrolamellar hepatocarcinoma. Intra-arterial chemo-therapy has been done for the patient about 6 months ago. Now he had none of the previous problems and his weight loss is reversed. Fibrolamellar hepatocellu-lar carcinoma should be kept in mind in young pa-tients with hypervascular liver masses and no history of hepatic diseases.

  13. Inhibiting effect of Astragalus polysaccharides on the functions of CD4+CD25highTreg cells in the tumor microenvironment of human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    LI Qiang; BAO Jian-min; LI Xiao-li; ZHANG Ti; SHEN Xiao-hong

    2012-01-01

    Background Astragalus polysaccharides (APS),the main active extract from Astragalus membranaceus (a traditional Chinese medicinal herb),is associated with a variety of immunomodulatory activities.The purpose of the present study was to examine the effect of APS on the function of Treg cells in the tumor microenvironment of human hepatocellular carcinoma (HCC) and to identify the pharmacologic mechanism of APS responsible for the anti-chemotactic activity in CD4+CD25highTreg cells in tumor site of HCC.Methods The prevalence of Treg in fresh tissue samples from 31 patients with HCC after radicalhepatectomy was detected.CD4,CD25 and CD127 were selected as Treg cell makers to phenotype cell populations.The expression of FOXp3 mRNA was also analyzed.The migration and proliferation of Treg cells were observed.Interleukin (IL)-4,IL-10,IFN-γ and SDF-1 in cell supernatant were detected.For all tests,functions of Treg cells were evaluated after treatment with APS.Results APS can inhibit the growth and proliferation of CD4+CD25+Treg cells in vitro in a dose- and time-dependent manner.APS may inhibit CD4+CD25+Treg cells through restoring the cytokine imbalance and reducing the expression of FOXp3 in local HCC microenvironments.SDF-1 played an important role in there recruitment of Treg cells into the tumor microenvironment of HCC.APS might have inhibiting effects on Treg cell migration by blocking SDF-1 or its receptor through the CXCR4/CXCL12 pathway.Conclusions The increase in numbers of tumor associated Treg cells might play a role in modulation of the immune response against HCC.APS can restore the cytokine balance in the tumor micro environment and suppress the expression of FOXp3 mRNA to inhibit the immune suppressive effects of Treg cells.The application of APS in the tumor microenvironment might act to enhance the anti-tumor effects of the immunotherapy-based methods,and consequently to increase the survival rate in HCC.

  14. Integrin α2β1 inhibits MST1 kinase phosphorylation and activates Yes-associated protein oncogenic signaling in hepatocellular carcinoma.

    Science.gov (United States)

    Wong, Kwong-Fai; Liu, Angela M; Hong, Wanjin; Xu, Zhi; Luk, John M

    2016-11-22

    The Hippo pathway regulates the down-stream target Yes-associated protein (YAP) to maintain organ homeostasis, which is commonly inactivated in many types of cancers. However, how cell adhesion dysregulates the Hippo pathway activating YAP oncogene in hepatocellular carcinoma (HCC) remains unclear. Our findings demonstrate that α2β1 integrin (but not other β1 integrins) expressed in HCC cells, after binding to collagen extracellular matrix, could inhibit MST1 kinase phosphorylation and activate YAP pro-oncogenic activities. Knockdown of integrin α2 gene (ITGA2) suppressed YAP targeted gene expression in vitro. α2β1 and collagen binding resulted in suppressing Hippo signaling of mammalian sterile 20-like kinase 1 (MST1) and Large tumor suppressor homolog 1 (LATS1) with concomitant activation of YAP-mediated connective tissue growth factor (CTGF) gene expression. In vitro kinase assay showed that MST1 is an immediate downstream target of integrin α2 with S1180 residue as the critical phosphorylation site. Clinical correlational analysis using a gene expression dataset of 228 HCC tumors revealed that ITGA2 expression was significantly associated with tumor progression, and co-expression with YAP targeted genes (AXL receptor tyrosine kinase, CTGF, cyclin D1, glypican 3, insulin like growth factor 1 receptor, and SRY-box 4) correlated with survivals of HCC patients. In conclusion, α2β1 integrin activation through cellular adhesion impacts the Hippo pathway in solid tumors and modulates MST1-YAP signaling cascade. Targeting integrin α2 holds promises for treating YAP-positive HCC.

  15. Fibrolamellar hepatocellular carcinoma with biliary tumor thrombus: an unreported association.

    Science.gov (United States)

    De Gaetano, Anna Maria; Nure, Erida; Grossi, Ugo; Frongillo, Francesco; Russo, Rosellina; Vecchio, Fabio Maria; Lirosi, Maria Carmen; Sganga, Gabriele; Felice, Carla; Bonomo, Lorenzo; Agnes, Salvatore

    2013-10-01

    Fibrolamellar hepatocellular carcinoma (FHCC) is a rare malignant tumor of hepatocyte origin occurring earlier in life than typical hepatocellular carcinoma (HCC). We describe a distinctive case of FHCC with biliary tumor thrombus (BTT) in a 25-year-old Caucasian patient, pointing out the imaging features supported by histopathology.

  16. Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Oliveri, Roberto S; Wetterslev, Jørn; Gluud, Christian

    2011-01-01

    Hepatocellular carcinoma (HCC) results in more than 600,000 deaths per year. Transarterial embolisation (TAE) and transarterial chemoembolisation (TACE) have become standard loco-regional treatments for unresectable HCC.......Hepatocellular carcinoma (HCC) results in more than 600,000 deaths per year. Transarterial embolisation (TAE) and transarterial chemoembolisation (TACE) have become standard loco-regional treatments for unresectable HCC....

  17. A polymeric nanoparticle formulation of curcumin in combination with sorafenib synergistically inhibits tumor growth and metastasis in an orthotopic model of human hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Bo [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Sun, Ding [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Department of Hepatobiliary Surgery, First Affiliated Hospital of Soochow University, Suzhou, 215004 (China); Sun, Chao; Sun, Yun-Fan; Sun, Hai-Xiang [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Zhu, Qing-Feng [The Johns Hopkins University School of Medicine, Division of Gastrointestinal and Liver Pathology, Baltimore, MD, 21205 (United States); Institute of Biomedical Sciences, Fudan University, Shanghai, 200032 (China); Yang, Xin-Rong [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Gao, Ya-Bo [Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032 (China); Tang, Wei-Guo [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Fan, Jia [Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032 (China); Institute of Biomedical Sciences, Fudan University, Shanghai, 200032 (China); Maitra, Anirban [The Sol Goldman Pancreatic Cancer Research Center, Departments of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 (United States); and others

    2015-12-25

    Curcumin, a yellow polyphenol extracted from the rhizome of turmeric root (Curcuma longa) has potent anti-cancer properties in many types of tumors with ability to reverse multidrug resistance of cancer cells. However, widespread clinical application of this agent in cancer and other diseases has been limited due to its poor aqueous solubility. The recent findings of polymeric nanoparticle formulation of curcumin (NFC) have shown the potential for circumventing the problem of poor solubility, however evidences for NFC's anti-cancer and reverse multidrug resistance properties are lacking. Here we provide models of human hepatocellular carcinoma (HCC), the most common form of primary liver cancer, in vitro and in vivo to evaluate the efficacy of NFC alone and in combination with sorafenib, a kinase inhibitor approved for treatment of HCC. Results showed that NFC not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. Moreover, in combination with sorafenib, NFC induced HCC cell apoptosis and cell cycle arrest. Mechanistically, NFC and sorafenib synergistically down-regulated the expression of MMP9 via NF-κB/p65 signaling pathway. Furthermore, the combination therapy significantly decreased the population of CD133-positive HCC cells, which have been reported as cancer initiating cells in HCC. Taken together, NanoCurcumin provides an opportunity to expand the clinical repertoire of this agent. Additional studies utilizing a combination of NanoCurcumin and sorafenib in HCC are needed for further clinical development. - Highlights: • Polymeric nanoparticle formulation of curcumin not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. • In combination with sorafenib, NanoCurcumin induced HCC cell apoptosis and cell cycle arrest. • NanoCurcumin and

  18. 1,25(OH)2D3 inhibits the progression of hepatocellular carcinoma via downregulating HDAC2 and upregulating P21(WAFI/CIP1).

    Science.gov (United States)

    Huang, Jian; Yang, Guozhen; Huang, Yunzhu; Kong, Weiying; Zhang, Shu

    2016-02-01

    Vitamin D, termed 1,25(OH)2D3 in it's active form, activity is associated with a reduced risk of hepatocellular carcinoma (HCC) and is an important immune regulator. However, the detail molecular mechanisms underlying the effects of 1,25(OH)2D3 on the progression of HCC are widely unknown. Histone deacetwylase 2 (HDAC2) is usually expressed at high levels in tumors, and its downregulation leads to high expression levels of cell cycle components, including p21(WAF1/Cip1), a well-characterized modulator, which is critical in cell senescence and apoptosis. The present study investigated whether vitamin D inhibits HCC via the regulation of HDAC2 and p21(WAF1/Cip1). Firstly, the toxic concentrations of 1,25(OH)2D3 were determined, according to trypan blue and [(3)H]thymidine incorporation assays. Secondly, HCC cells lines were treated with different concentrations of 1,25(OH)2D3. The expression of HDAC2 was either silenced via short hairpin (sh)RNA or induced by transfection of plasmids expressing the HDAC2 gene in certain HCC cells. Finally the mRNA and protein levels of HDAC2 and p21(WAF1/Cip1) were measured using reverse transcription-quantitative polymerase chain reaction and western blot analyses. The results revealed that 1,25(OH)2D3 treatment reduced the expression of HDAC2 and increased the expression of p21(WAF1/Cip1), in a dose-dependent manner, resulting in the reduction of HCC growth. Elevated levels of HDAC2 reduced the expression of p21(WAF1/Cip1), resulting in an increase in HCC growth. HDAC2 shRNA increased the expression of p21(WAF1/Cip1), resulting in reduction in HCC growth. Thus, 1,25(OH)2D3 exerted antitumorigenic effects through decreasing the expression levels of HDAC2 and increasing the expression of p21(WAF1/Cip1), which inhibited the development of HCC and may indicate the possible underlying mechanism. These results suggest that vitamin D3 may be developed as a potential drug for effective therapy in the treatment of HCC.

  19. Astrocyte Elevated Gene-1 (AEG-1) Contributes to Non-thyroidal Illness Syndrome (NTIS) Associated with Hepatocellular Carcinoma (HCC)*

    OpenAIRE

    Srivastava, Jyoti; Robertson, Chadia L.; Gredler, Rachel; Siddiq, Ayesha; Rajasekaran, Devaraja; Akiel, Maaged A; Emdad, Luni; Mas, Valeria; Mukhopadhyay, Nitai D.; FISHER, PAUL B.; Sarkar, Devanand

    2015-01-01

    Background: Astrocyte elevated gene-1 (AEG-1) inhibits retinoid X receptor (RXR) function and is overexpressed in human hepatocellular carcinoma (HCC), which is associated with non-thyroidal illness syndrome (NTIS).

  20. Aflatoxins as a cause of hepatocellular carcinoma.

    Science.gov (United States)

    Kew, Michael C

    2013-09-01

    Aflatoxins, metabolites of the fungi Aspergillus flavus and Aspergillus parasiticus, are frequent contaminants of a number of staple foods, particularly maize and ground nuts, in subsistence farming communities in tropical and sub-tropical climates in sub-Saharan Africa, Eastern Asia and parts of South America. Contamination of foods occurs during growth and as a result of storage in deficient or inappropriate facilities. These toxins pose serious public health hazards, including the causation of hepatocellular carcinoma by aflatoxin B1. Exposure begins in utero and is life-long. The innocuous parent molecule of the fungus is converted by members of the cytochrome p450 family into mutagenic and carcinogenic intermediates. Aflatoxin-B1 is converted into aflatoxin B1-8,9 exo-epoxide, which is in turn converted into 8,9-dihydroxy-8-(N7) guanyl-9-hydroxy aflatoxin B1 adduct. This adduct is metabolized into aflatoxin B1 formaminopyrimidine adduct. These adducts are mutagenic and carcinogenic. In addition, an arginine to serine mutation at codon 249 of the p53 tumor suppressor gene is produced, abrogating the function of the tumor suppressor gene, and contributing to hepatocarcinogenesis. Aflatoxin B1 acts synergistically with hepatitis B virus in causing hepatocellular carcinoma. A number of interactions between the two carcinogens may be responsible for this action, including integration of hepatitis B virus x gene and its consequences, as well as interference with nucleotide excision repair, activation of p21waf1/cip1, generation of DNA mutations, and altered methylation of genes. But much remains to be learnt about the precise pathogenetic mechanisms responsible for aflatoxin B1-induced hepatocellular carcinoma as well as the interaction between the toxin and hepatitis B virus in causing the tumor.

  1. Innovative surgical approaches for hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Riccardo; Memeo; Nicola; de’Angelis; Vito; de; Blasi; Zineb; Cherkaoui; Oronzo; Brunetti; Vito; Longo; Tullio; Piardi; Daniele; Sommacale; Jacques; Marescaux; Didier; Mutter; Patrick; Pessaux

    2016-01-01

    Hepatocellular carcinoma(HCC)is the sixth most common cancer worldwide,with an increasing diffusion in Europe and the United States.The management of such a cancer is continuously progressing and the objective of this paper is to evaluate innovation in the surgical treatment of HCC.In this review,we will analyze the modern concept of preoperative management,the role of laparoscopic and robotic surgery,the intraoperative use of three dimensional models and augmented reality,as well as the potential application of fluorescence.

  2. Hepatocellular Carcinoma: Therapeutic Guidelines and Medical Treatment

    Science.gov (United States)

    Kudo, Masatoshi; Trevisani, Franco; Abou-Alfa, Ghassan K; Rimassa, Lorenza

    2016-01-01

    Western and Eastern perspectives on therapeutic guidelines for hepatocellular carcinoma (HCC) have many commonalities but may also differ in certain aspects, as described in this article. In view of the limited therapeutic options for advanced HCC, evidence-based therapies are few, and thus there is a dependence on consensus-based guidelines. This article focuses on the Italian Association for the Study of the Liver guidelines and the Japanese approaches to therapy, while drawing attention to certain controversies from other academic bodies where applicable and appropriate. PMID:27995084

  3. Hepatitis C Virus and Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Masao Omata

    2013-01-01

    Full Text Available Hepatitis C virus (HCV, a hepatotropic virus, is a single stranded-positive RNA virus of ~9,600 nt. length belonging to the Flaviviridae family. HCV infection causes acute hepatitis, chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC. It has been reported that HCV-coding proteins interact with host-cell factors that are involved in cell cycle regulation, transcriptional regulation, cell proliferation and apoptosis. Severe inflammation and advanced liver fibrosis in the liver background are also associated with the incidence of HCV-related HCC. In this review, we discuss the mechanism of hepatocarcinogenesis in HCV-related liver diseases.

  4. Epigenetics of hepatocellular carcinoma: a new horizon

    Institute of Scientific and Technical Information of China (English)

    LIU Wei-ren; SHI Ying-hong; PENG Yuan-fei; FAN Jia

    2012-01-01

    Epigenetic changes refer to stable alterations in gene expression with no underlying modifications in the genetic sequence itself.It has become clear that not only gene variations but also epigenetic modifications may contribute to varied diseases,including cancer.This review will provide an overview of how epigenetic factors,including genomic DNA methylation,histone modifications,and miRNA regulation,contribute to hepatocellular carcinoma (HCC) dissemination,invasion,and metastasis.Additionally,the reversal of dysregulated epigenetic changes has emerged as a potential strategy for the treatment of HCC,and we will summarize the latest epigenetic therapies for HCC.

  5. Non-viral causes of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Wojciech; Blonski; David; S; Kotlyar; Kimberly; A; Forde

    2010-01-01

    Hepatocellular carcinoma(HCC) is the most common primary liver malignancy and represents an international public health concern as one of the most deadly cancers worldwide.The main etiology of HCC is chronic infection with hepatitis B and hepatitis C viruses.However,there are other important factors that contribute to the international burden of HCC.Among these are obesity,diabetes,non-alcoholic steatohepatitis and dietary exposures.Emerging evidence suggests that the etiology of many cases of HCC is in fac...

  6. Microwave ablation of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Although surgical resection is still the optimal treatmentoption for early-stage hepatocellular carcinoma(HCC) in patients with well compensated cirrhosis,thermal ablation techniques provide a valid nonsurgicaltreatment alternative, thanks to their minimalinvasiveness, excellent tolerability and safety profile,proven efficacy in local disease control, virtuallyunlimited repeatability and cost-effectiveness. Differentenergy sources are currently employed in clinics asphysical agents for percutaneous or intra-surgicalthermal ablation of HCC nodules. Among them, radiofrequency(RF) currents are the most used, whilemicrowave ablations (MWA) are becoming increasinglypopular. Starting from the 90s', RF ablation (RFA) rapidlybecame the standard of care in ablation, especially inthe treatment of small HCC nodules; however, RFAexhibits substantial performance limitations in thetreatment of large lesions and/or tumors located nearmajor heat sinks. MWA, first introduced in the FarEastern clinical practice in the 80s', showing promisingresults but also severe limitations in the controllabilityof the emitted field and in the high amount of poweremployed for the ablation of large tumors, resultingin a poor coagulative performance and a relativelyhigh complication rate, nowadays shows better resultsboth in terms of treatment controllability and of overallcoagulative performance, thanks to the improvementof technology. In this review we provide an extensiveand detailed overview of the key physical and technicalaspects of MWA and of the currently available systems,and we want to discuss the most relevant published dataon MWA treatments of HCC nodules in regard to clinicalresults and to the type and rate of complications, both inabsolute terms and in comparison with RFA.

  7. Diphenyl difluoroketone: a potent chemotherapy candidate for human hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Yingjian Liang

    Full Text Available Diphenyl difluoroketone (EF24, a molecule having structural similarity to curcumin, was recently reported to inhibit proliferation of various cancer cells significantly. Here we try to determine the effect and mechanism of EF24 on hepatocellular carcinoma. 2 µM EF24 was found to inhibit the proliferation of PLC/PRF/5, Hep3B, HepG2, SK-HEP-1 and Huh 7 cell lines. However, even 8 µM EF24 treatment did not affect the proliferation of normal liver LO2 cells. Accordingly, 20 mg/kg/d EF24 inhibited the growth of the tumor xenografts conspicuously while causing no apparent change in liver, spleen or body weight. In addition, significant apoptosis and G(2/M phase cell cycle arrest were found using flow cytometry. Besides, caspases and PARP activation and features typical of apoptosis including fragmented nuclei with condensed chromatin were also observed. Furthermore, the mechanism was targeted at the reduction of nuclear factor kappa b (NF-κB pathway and the NF-κB-regulated gene products Bcl-2, COX-2, Cyclin B1. Our study has offered a strategy that EF24 being a therapeutic agent for hepatocellular carcinoma.

  8. Synergistic effect of interventing insulin-like growth factor-Ⅰ receptor activation combined with anti-cancer drugs in inhibiting the proliferation of hepatocellular carcinoma cells

    Directory of Open Access Journals (Sweden)

    CAI Yin

    2016-08-01

    Full Text Available ObjectiveTo investigate the intervention of gene transcription of insulin-like growth factor-Ⅰ receptor (IGF-ⅠR and its synergistic effect with anti-cancer drugs in inhibiting the proliferation of hepatocellular carcinoma (HCC cells. MethodsThe HBV-positive HCC PLC/PRF/5 and HBV-negative Bel-7404 cells were transfected with the efficient plasmid pGPU6/GFP/Neo-IGF-ⅠR-shRNA. Fluorescent quantitative RT-PCR and Western blot were used to measure mRNA and protein expression, the Cell Counting Kit-8 was used to analyze cell proliferation, and flow cytometry and Annexin-V-PE/7-ADD were used to analyze cell cycle and apoptosis. The t-test was used for comparison of continuous data between groups, the Fisher′s exact test was used for comparison of categorical data between groups. ResultsThe efficiency of IGF-ⅠR shRNA transfection was 71% in HCC PLC/PRF/5 cells and 90% in Bel-7404 cells, and both cells showed reductions in the mRNA and protein expression of IGF-ⅠR. The intervention group showed a significant inhibition compared with the negative control group, and the 72-hour inhibition rates of Bel-7404 cells and PLC/PRF/5 cells showed significant differences between the two groups (inhibition rates of Bel-7404 cells: 615%±17%vs 112%±09%, t=5.493, P<0.05; inhibitionrates of PLC/PRF/5 cells: 639%±39%vs 95%±11%, t=19.244, P<0.001. The intervention group showed a significantly higher apoptosis rate of Bel-7404 cells than the blank control group (35.96% vs 12.16%, P<0.001 and the negative control group (3596% vs 943%, P<0.001, as well as a significantly higher apoptosis rate of PLC/PRF/5 cells than the blank control group (4484% vs 662%, P<0.001 and the negative control group (44.84% vs 4.02%, P<0.001. The co-intervention group showed significantly higher percentages of Bel-7404 cells and PLC/PRF/5 cells in G0/G1 phase than the negative control group (59.0%±1.3% vs 484%±0.8%, t=12.032, P

  9. MicroRNA let-7c Inhibits Cell Proliferation and Induces Cell Cycle Arrest by Targeting CDC25A in Human Hepatocellular Carcinoma.

    Directory of Open Access Journals (Sweden)

    Xiuming Zhu

    Full Text Available Down-regulation of the microRNA let-7c plays an important role in the pathogenesis of human hepatocellular carcinoma (HCC. The aim of the present study was to determine whether the cell cycle regulator CDC25A is involved in the antitumor effect of let-7c in HCC. The expression levels of let-7c in HCC cell lines were examined by quantitative real-time PCR, and a let-7c agomir was transfected into HCC cells to overexpress let-7c. The effects of let-7c on HCC proliferation, apoptosis and cell cycle were analyzed. The in vivo tumor-inhibitory efficacy of let-7c was evaluated in a xenograft mouse model of HCC. Luciferase reporter assays and western blotting were conducted to identify the targets of let-7c and to determine the effects of let-7c on CDC25A, CyclinD1, CDK6, pRb and E2F2 expression. The results showed that the expression levels of let-7c were significantly decreased in HCC cell lines. Overexpression of let-7c repressed cell growth, induced cell apoptosis, led to G1 cell cycle arrest in vitro, and suppressed tumor growth in a HepG2 xenograft model in vivo. The luciferase reporter assay showed that CDC25A was a direct target of let-7c, and that let-7c inhibited the expression of CDC25A protein by directly targeting its 3' UTR. Restoration of CDC25A induced a let-7c-mediated G1-to-S phase transition. Western blot analysis demonstrated that overexpression of let-7c decreased CyclinD1, CDK6, pRb and E2F2 protein levels. In conclusion, this study indicates that let-7c suppresses HCC progression, possibly by directly targeting the cell cycle regulator CDC25A and indirectly affecting its downstream target molecules. Let-7c may therefore be an effective therapeutic target for HCC.

  10. ZKSCAN1 gene and its related circular RNA (circZKSCAN1) both inhibit hepatocellular carcinoma cell growth, migration, and invasion but through different signaling pathways.

    Science.gov (United States)

    Yao, Zhicheng; Luo, Jingyan; Hu, Kunpeng; Lin, Jizong; Huang, He; Wang, Qiangliang; Zhang, Peng; Xiong, Zhiyong; He, Chonghua; Huang, Zejian; Liu, Bo; Yang, Yang

    2017-04-01

    There is increasing evidence that circular RNA (circRNA) are involved in cancer development, but the regulation and function of human circRNA remain largely unknown. In this study, we demonstrated that ZKSCAN1, a zinc finger family gene, is expressed in both linear and circular (circZKSCAN1) forms of RNA in human hepatocellular carcinoma (HCC) tissues and cell lines. Here, we analyzed a cohort of 102 patients and found that expression of both ZKSCAN1mRNA and circZKSCAN1 was significantly lower (P < 0.05) in the HCC samples compared with that in matched adjacent nontumorous tissues by reverse transcription PCR (RT-PCR). The low expression level of ZKSCAN1 was only associated with tumor size (P = 0.032), while the cirZKSCAN1 levels varied in patients with different tumor numbers (P < 0.01), cirrhosis (P = 0.031), vascular invasion (P = 0.002), or microscopic vascular invasion (P = 0.002), as well as with the tumor grade (P < 0.001). Silencing both ZKSCAN1mRNA and circZKSCAN1 promoted cell proliferation, migration, and invasion. In contrast, overexpression of both forms of RNA repressed HCC progression in vivo and in vitro. Silencing or overexpression of both forms of RNA did not interfere with each other. RNA-seq revealed a very different molecular basis for the observed effects; ZKSCAN1mRNA mainly regulated cellular metabolism, while circZKSCAN1 mediated several cancer-related signaling pathways, suggesting a nonredundant role for ZKSCAN1mRNA and circRNA. In conclusion, our results revealed two post-translational products (ZKSCAN1mRNA and circZKSCAN1) that cooperated closely with one another to inhibit growth, migration, and invasion of HCC. cirZKSCAN1 might be a useful marker for the diagnosis of HCC.

  11. Metabolic characterization of hepatocellular carcinoma using nontargeted tissue metabolomics.

    Science.gov (United States)

    Huang, Qiang; Tan, Yexiong; Yin, Peiyuan; Ye, Guozhu; Gao, Peng; Lu, Xin; Wang, Hongyang; Xu, Guowang

    2013-08-15

    Hepatocellular carcinoma has a poor prognosis due to its rapid development and early metastasis. In this report, we characterized the metabolic features of hepatocellular carcinoma using a nontargeted metabolic profiling strategy based on liquid chromatography-mass spectrometry. Fifty pairs of liver cancer samples and matched normal tissues were collected from patients having hepatocellular carcinoma, including tumor tissues, adjacent noncancerous tissues, and distal noncancerous tissues, and 105 metabolites were filtered and identified from the tissue metabolome. The principal metabolic alternations in HCC tumors included elevated glycolysis, gluconeogenesis, and β-oxidation with reduced tricarboxylic acid cycle and Δ-12 desaturase. Furthermore, increased levels of glutathione and other antioxidative molecules, together with decreased levels of inflammatory-related polyunsaturated fatty acids and phospholipase A2, were observed. Differential metabolite levels in tissues were tested in 298 serum specimens from patients with chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Betaine and propionylcarnitine were confirmed to confer good diagnostic potential to distinguish hepatocellular carcinoma from chronic hepatitis and cirrhosis. External validation of cirrhosis and hepatocellular carcinoma serum specimens further showed that this combination biomarker is useful for diagnosis of hepatocellular carcinoma with a supplementary role to α-fetoprotein.

  12. Hepatocellular carcinoma: epidemiology, biology, diagnosis, and therapies.

    Science.gov (United States)

    Gomes, Marcos António; Priolli, Denise Gonçalves; Tralhão, José Guilherme; Botelho, Maria Filomena

    2013-01-01

    Hepatocellular carcinoma is the fifth most common cancer in men and the seventh in women, as is diagnosed in more than half a million individuals worldwide every year. In Portugal, its incidence and mortality rates are low compared to other types of cancers. In Brazil, in the city of São Paulo, according to data released by the Brazilian Unified Health System (Sistema Único de Saúde - SUS), the incidence of primary liver cancer was 2.07/100,000 inhabitants. Although the vast majority of cases (85%) mainly affect developing countries, especially where infection by hepatitis B virus (HBV) is endemic, the incidence in developed countries is increasing. This pathology is associated with several risk factors, not only environmental but also genetic, generating an increasing interest in attaining a better understanding of this disease, which is still associated with very late diagnosis and poor prognosis. Of the available treatments, few patients benefit from their scanty advantages, increasingly stimulating research of new forms of treatment against this disease. This review aimed to briefly but fully identify risk factors, molecular and biochemical pathways, pathophysiology, diagnosis, and possible clinical approaches of hepatocellular carcinoma. Copyright © 2013 Elsevier Editora Ltda. All rights reserved.

  13. GPC-3 in hepatocellular carcinoma: current perspectives

    Directory of Open Access Journals (Sweden)

    Wu Y

    2016-11-01

    Full Text Available Yongle Wu,1 Hui Liu,2 Huiguo Ding1 1Department of Gastroenterology and Hepatology, 2Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, People’s Republic of China Abstract: Glypican-3 (GPC3, a member of heparan sulfate proteoglycans, attaches to the cell membrane and is frequently observed to be elevated in hepatocellular carcinoma (HCC. However, GPC3 is not detected in normal liver tissues and benign liver lesions. Consequently, GPC3 is currently being used as a diagnostic biomarker and HCC-specific positron emission computed tomography probe to identify HCCs in normal liver tissues and benign liver lesions. The overexpression of GPC-3 in serum or liver tissue also predicts poor prognosis for HCC patients. In addition, GPC3 promotes HCC growth and metastasis by activating the canonical Wnt and other signaling pathways. Targeting of GPC3, including GC33, HN3 and YP7, might offer new immunotherapeutic tools for HCC treatment. Keywords: glypican-3, hepatocellular carcinoma, diagnostics, prognosis, immunotherapy

  14. Curcumin Suppresses Phthalate-Induced Metastasis and the Proportion of Cancer Stem Cell (CSC)-like Cells via the Inhibition of AhR/ERK/SK1 Signaling in Hepatocellular Carcinoma.

    Science.gov (United States)

    Tsai, Cheng-Fang; Hsieh, Tsung-Hua; Lee, Jau-Nan; Hsu, Chia-Yi; Wang, Yu-Chih; Kuo, Kung-Kai; Wu, Hua-Lin; Chiu, Chien-Chih; Tsai, Eing-Mei; Kuo, Po-Lin

    2015-12-09

    Recent evidence indicating that phthalates promote cancer development, including cell proliferation, migration, and invasion, has raised public health concerns. Here, we show that bis(2-ethylhexyl) phthalate promotes the migration, invasion, and epithelial-mesenchymal transition of hepatocellular carcinoma cells. In addition, bis(2-ethylhexyl) phthalate increased the proportion of cancer stem cell (CSC)-like cells and stemness maintenance in vitro as well as tumor growth and metastasis in vivo. The various activities of curcumin, including anticancer, anti-inflammation, antioxidation, and immunomodulation, have been investigated extensively. Curcumin suppressed phthalate-induced cell migration, invasion, and epithelial-mesenchymal transition, decreased the proportion of CSC-like cells in hepatocellular carcinoma cell lines in vitro, and inhibited tumor growth and metastasis in vivo. We also reveal that curcumin suppressed phthalate-induced migration, invasion, and CSC-like cell maintenance through inhibition of the aryl hydrocarbon receptor/ERK/SK1/S1P3 signaling pathway. Our results suggest that curcumin may be a potential antidote for phthalate-induced cancer progression.

  15. Primary hepatocellular carcinoma and metabolic syndrome:An update

    Institute of Scientific and Technical Information of China (English)

    Rubayat; Rahman; Ghassan; M; Hammoud; Ashraf; A; Al-mashhrawi; Khulood; T; Ahmed; Jamal; A; Ibdah

    2013-01-01

    Hepatocellular carcinoma(HCC) is the most common primary liver malignancy. The incidence of hepatocellular carcinoma has increased dramatically by 80% over the past two decades in the United States. Numerous basic science and clinical studies have documented a strong association between hepatocellular carcinoma and the metabolic syndrome. These studies have documented that, in most patients, non-alcoholic fatty liver disease is the hepatic manifestation of the metabolic syndrome, which may progress to hepatocellular carcinoma through the cirrhotic process. However, minority of patients with non-alcoholic fatty liver disease may progress to hepatocellular carcinoma without cirrhosis.This review summarizes the current literature of the link between hepatocellular carcinoma and metabolic syndrome with special emphasis on various components of the metabolic syndrome including risk of association with obesity, diabetes mellitus, hyperlipidemia,and hypertension. Current understanding of pathophysiology, clinical features, treatments, outcomes,and surveillance of hepatocellular carcinoma in the background of metabolic syndrome and non-alcoholic fatty liver disease is reviewed. With the current epidemic of metabolic syndrome, the number of patients with non-alcoholic fatty liver disease is increasing.Subsequently, it is expected that the incidence and prevalence of HCC will also increase. It is very important for the scientific community to shed more light on the pathogenesis of HCC with metabolic syndrome,both with and without cirrhosis. At the same time it is also important to quantify the risk of hepatocellular carcinoma associated with the metabolic syndrome in a prospective setting and develop surveillance recommendations for detection of hepatocellular carcinoma in patients with metabolic syndrome.

  16. The Role of Receptor for Advanced Glycation End Products (RAGE in the Proliferation of Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Wei Tian

    2012-05-01

    Full Text Available The receptor for advanced glycation end products (RAGE is oncogenic and overexpressed in human cancers, but its role in hepatocellular carcinoma remains unclear. Here we demonstrated that RAGE is overexpressed in primary hepatocellular carcinoma (PHC compared to adjacent para-neoplastic liver samples. Serum endogenous secretory RAGE levels were also increased in PHC patients (p < 0.01. Moreover, we demonstrated that RAGE regulates cellular proliferation in Hepatocellular carcinoma (HCC. Knockdown of RAGE by specific siRNA inhibited cellular growth in the hepatocellular carcinoma cell line, Huh7, whereas the RAGE ligand, high mobility group box 1 protein (HMGB1 increased cellular proliferation. In addition, knockdown of RAGE by siRNA arrested cells in the G1 phase and inhibited DNA synthesis (p < 0.01, while HMGB1 protein decreased the number of cells in the G1 phase and increased the number in the S phase (p < 0.05. Furthermore, quantitative real time RT-PCR (qRT-PCR and Western Blot results demonstrated that RAGE and HMGB1 positively regulate NF-κB p65 expression in Huh7 cells. These studies suggest that RAGE and RAGE ligands are important targets for therapeutic intervention in hepatocellular carcinoma.

  17. Gingival metastasis from primary hepatocellular carcinoma. Report of a case.

    Science.gov (United States)

    Wedgwood, D; Rusen, D; Balk, S

    1979-03-01

    A case of primary hepatocellular carcinoma metastatic to the gingiva is described. Hepatocellular carcinoma is an uncommon malignancy, generally occurring in a cirrhotic liver, which rarely metastasizes to the maxillofacial area. Of eight such cases in the English-language literature, the present case is the fourth involving metastasis to the gingiva. Hepatocellular carcinoma would seem to metastasize with equal frequency to the gingiva and to the mandibular bone. In the case described, histologic examination of the gingival lesion definitively established the diagnosis following somewhat equivocal results of needle biopsy of the liver.

  18. Micronutrient Synergy in the Fight against Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Aleksandra Niedzwiecki

    2012-03-01

    Full Text Available The incidence of hepatocellular carcinoma (HCC, once thought to be a rare tumor in North America, has rapidly increased in recent years in the United States. Current treatment modalities to halt the progression of this disease are only marginally effective. The mainstay treatment is liver transplantation, which is often confronted with donor shortage. Invasion, metastasis and recurrence contribute to the high mortality rate of this disease. Matrix metalloproteinases (MMPs that degrade the extracellular matrix (ECM have been associated with the progression, invasion and metastasis of the disease. We have developed strategies to strengthen the ECM collagen and inhibit MMPs through micronutrients such as lysine, proline and ascorbic acid. Addition of epigallocatechin gallate or green tea extract to these micronutrients synergistically enhanced anti-carcinogenic activity in HepG2 cells. Addition of certain other micronutrients, such as N-acetylcysteine, selenium, copper and zinc (NM synergistically enhanced the anticancer activity of the mixture in a model of hepatocellular carcinoma using HepG2 cells. In vitro studies using HepG2 demonstrated that NM was very effective in inhibiting cell proliferation (by MTT assay, MMPs secretion (by gelatinase zymography, cell invasion (through Matrigel and induction of apoptosis (by live green caspase. In addition, NM was shown to down-regulate urokinase plasminogen activator (by fibrin zymography and up-regulate tissue inhibitors of metalloproteinases (by reverse zymography in another HCC cell line, SK-Hep-1. MMP-2 and MMP-9 activities were further modulated by phorbol 12-myristate 13-acetate (PMA induction and inhibited by NM. In previous studies, NM inhibited Sk-Hep-1 xenografts in nude mice and also inhibited hepatic metastasis of B16FO melanoma cells. Our results suggest that NM is an excellent candidate for therapeutic use in the treatment HCC by inhibiting critical parameters in cancer development and

  19. Micronutrient Synergy in the Fight against Hepatocellular Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Roomi, M. Waheed; Roomi, Nusrath W.; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra, E-mail: a.niedz@drrath.com; Rath, Matthias [Dr. Rath Research Institute, 1260 Memorex Drive, Santa Clara, CA 95050 (United States)

    2012-03-23

    The incidence of hepatocellular carcinoma (HCC), once thought to be a rare tumor in North America, has rapidly increased in recent years in the United States. Current treatment modalities to halt the progression of this disease are only marginally effective. The mainstay treatment is liver transplantation, which is often confronted with donor shortage. Invasion, metastasis and recurrence contribute to the high mortality rate of this disease. Matrix metalloproteinases (MMPs) that degrade the extracellular matrix (ECM) have been associated with the progression, invasion and metastasis of the disease. We have developed strategies to strengthen the ECM collagen and inhibit MMPs through micronutrients such as lysine, proline and ascorbic acid. Addition of epigallocatechin gallate or green tea extract to these micronutrients synergistically enhanced anti-carcinogenic activity in HepG2 cells. Addition of certain other micronutrients, such as N-acetylcysteine, selenium, copper and zinc (NM) synergistically enhanced the anticancer activity of the mixture in a model of hepatocellular carcinoma using HepG2 cells. In vitro studies using HepG2 demonstrated that NM was very effective in inhibiting cell proliferation (by MTT assay), MMPs secretion (by gelatinase zymography), cell invasion (through Matrigel) and induction of apoptosis (by live green caspase). In addition, NM was shown to down-regulate urokinase plasminogen activator (by fibrin zymography) and up-regulate tissue inhibitors of metalloproteinases (by reverse zymography) in another HCC cell line, SK-Hep-1. MMP-2 and MMP-9 activities were further modulated by phorbol 12-myristate 13-acetate (PMA) induction and inhibited by NM. In previous studies, NM inhibited Sk-Hep-1 xenografts in nude mice and also inhibited hepatic metastasis of B16FO melanoma cells. Our results suggest that NM is an excellent candidate for therapeutic use in the treatment HCC by inhibiting critical parameters in cancer development and progression

  20. ENMD-1198, a novel tubulin-binding agent reduces HIF-1alpha and STAT3 activity in human hepatocellular carcinoma(HCC) cells, and inhibits growth and vascularization in vivo.

    Science.gov (United States)

    Moser, Christian; Lang, Sven A; Mori, Akira; Hellerbrand, Claus; Schlitt, Hans J; Geissler, Edward K; Fogler, William E; Stoeltzing, Oliver

    2008-07-23

    Hepatocellular carcinoma (HCC) represents a highly vascularized tumor entity and the process of angiogenesis is essential for the growth of HCC. Importantly, the pro-angiogenic transcription factors HIF-1alpha and STAT3 have been implicated in HCC progression, thus representing interesting targets for molecular targeted therapy. We hypothesized that therapeutic inhibition of HIF-1alpha could be achieved by using a novel tubulin-binding agent (ENMD-1198). ENMD-1198 is an analog of 2-methoxyestradiol (2ME2) with antiproliferative and antiangiogenic activity. The human HCC cell lines HUH-7 and HepG2 were used for experiments. Effects of ENMD-1198 on constitutive and inducible (hypoxia, growth factors) activation of signaling cascades, including HIF-1alpha and STAT3, were investigated by Western blotting. Changes in VEGF expression were determined by real-time PCR. Effects of ENMD-1198 on cancer cell migration and invasion were evaluated in in vitro-assays. The growth-inhibitory effects of ENMD-1198 (200 mg/kg/day) were determined in a subcutaneous tumor model (HUH-7). ENMD-1198 inhibited the phosphorylation of MAPK/Erk, PI-3K/Akt and FAK. Moreover, activation of HIF-1alpha and STAT3 was dramatically reduced by ENMD-1198, which resulted in lower VEGF mRNA expression (P < 0.05). In addition, tumor cell migratory and invasive properties were significantly inhibited (P < 0.05, for both). In vivo, treatment with ENMD-1198 led to a significant reduction in tumor growth, tumor vascularization, and numbers of proliferating tumor cells (P < 0.05 for all). The novel microtubule destabilizing agent ENMD-1198 is suitable for inhibiting HIF-1alpha and STAT3 in human HCC cells and leads to reduced tumor growth and vascularization in vivo. Hence, inhibition of HIF-1alpha and STAT3 could prove valuable for therapy of hepatocellular carcinoma.

  1. Radiosensitivity of hepatocellular carcinoma; Radiosensibilite des cancers du foie

    Energy Technology Data Exchange (ETDEWEB)

    Hennequin, C.; Quero, L.; Rivera, S. [Service de cancerologie-radiotherapie, hopital Saint-Louis, 1, avenue Claude-Vellefeaux, 75475 Paris (France)

    2011-02-15

    The frequency of hepatocellular carcinoma (HCC) is increasing in the western world and the role of radiotherapy is more and more discussed. Classically, hepatocellular carcinoma was considered as a radioresistant tumour: in fact, modern radio-biologic studies, performed on cell lines directly established from patients, showed that hepatocellular carcinoma has the same radiosensitivity than the other epithelial tumours. From clinical studies, its {alpha}/{beta} ratio has been estimated to be around 15 Gy. Radiosensitivity of normal hepatic parenchyma is now well evaluated and some accurate NTCP models are available to guide hepatic irradiation. The biology of hepatocellular carcinoma is also better described: the combination of radiotherapy and targeted therapies will be a promising approach in the near future. (authors)

  2. Hepatocellular carcinoma : Dutch guideline for surveillance, diagnosis and therapy

    NARCIS (Netherlands)

    Eskens, F. A. L. M.; van Erpecum, K. J.; de Jong, K. P.; van Delden, O. M.; Klumpen, H. J.; Verhoef, C.; Jansen, P. L. M.; van den Bosch, M. A. A. J.; Romero, A. Mendez; Verheij, J.; Bloemena, E.; de Man, R. A.

    2014-01-01

    Hepatocellular carcinoma (HCC) is rare in the Netherlands, even though the incidence has increased quite sharply in recent years. Standard treatment options consist of surgery, orthotopic liver transplantation, radiofrequency ablation, transarterial chemoembolisation (TACE) and systemic therapy with

  3. Hepatocellular carcinoma : Dutch guideline for surveillance, diagnosis and therapy

    NARCIS (Netherlands)

    Eskens, F. A. L. M.; van Erpecum, K. J.; de Jong, K. P.; van Delden, O. M.; Klumpen, H. J.; Verhoef, C.; Jansen, P. L. M.; van den Bosch, M. A. A. J.; Romero, A. Mendez; Verheij, J.; Bloemena, E.; de Man, R. A.

    Hepatocellular carcinoma (HCC) is rare in the Netherlands, even though the incidence has increased quite sharply in recent years. Standard treatment options consist of surgery, orthotopic liver transplantation, radiofrequency ablation, transarterial chemoembolisation (TACE) and systemic therapy with

  4. Percutaneous local therapies for hepatocellular carcinoma impair gastric function

    Institute of Scientific and Technical Information of China (English)

    Fumihiko Kinekawa; Shigeki Kuriyama; Kazuya Matsuda; Tsutomu Masaki; Kazutaka Kurokohchi; Hirohito Yoneyama; Hideyuki Inoue; Hirohide Kurata; Yoshihito Uchida; Seishiro Watanabe

    2006-01-01

    @@ TO THE EDITOR Percutaneous local therapies, such as percutaneous ethanol injection (PEI), microwave coagulation and radiofrequency ablation (RFA), are frequently used worldwide for the treatment of hepatocellular carcinoma (HCC) because of their high effectiveness.

  5. VEGF in hepatocellular carcinoma and surrounding cirrhotic liver tissues

    Institute of Scientific and Technical Information of China (English)

    Muriel Mathonnet; Bernard Descottes; Denis Valleix; Francois Labrousse; Yves Denizot

    2006-01-01

    @@ TO THE EDITOR We read with a great interest the recent work of Deli and colleagues.[1] in the World Journal of Gastroenterology reporting vascular endothelial growth factor (VEGF) expression in hepatocellular carcinoma (HCC) and cirrhotic liver tissues.

  6. Infection of hepatitis C virus genotypes in hepatocellular carcinoma ...

    African Journals Online (AJOL)

    Jane

    2011-08-08

    Aug 8, 2011 ... liver cirrhosis and hepatocellular carcinoma (HCC) over the course of 20 to 30 years if not ... immunodeficiency virus (HIV), smoking and obesity. (Idrees et al., 2008; 2009). ... cancer were also documented. Possible sources of ...

  7. Immunization With AFP + GM CSF Plasmid Prime and AFP Adenoviral Vector Boost in Patients With Hepatocellular Carcinoma

    Science.gov (United States)

    2015-12-01

    Hepatocellular Carcinoma; Hepatoma; Liver Cancer, Adult; Liver Cell Carcinoma; Liver Cell Carcinoma, Adult; Cancer of Liver; Cancer of the Liver; Cancer, Hepatocellular; Hepatic Cancer; Hepatic Neoplasms; Hepatocellular Cancer; Liver Cancer; Neoplasms, Hepatic; Neoplasms, Liver

  8. ENMD-1198, a novel tubulin-binding agent reduces HIF-1alpha and STAT3 activity in human hepatocellular carcinoma(HCC cells, and inhibits growth and vascularization in vivo

    Directory of Open Access Journals (Sweden)

    Schlitt Hans J

    2008-07-01

    Full Text Available Abstract Background Hepatocellular carcinoma (HCC represents a highly vascularized tumor entity and the process of angiogenesis is essential for the growth of HCC. Importantly, the pro-angiogenic transcription factors HIF-1α and STAT3 have been implicated in HCC progression, thus representing interesting targets for molecular targeted therapy. We hypothesized that therapeutic inhibition of HIF-1α could be achieved by using a novel tubulin-binding agent (ENMD-1198. ENMD-1198 is an analog of 2-methoxyestradiol (2ME2 with antiproliferative and antiangiogenic activity. Methods The human HCC cell lines HUH-7 and HepG2 were used for experiments. Effects of ENMD-1198 on constitutive and inducible (hypoxia, growth factors activation of signaling cascades, including HIF-1α and STAT3, were investigated by Western blotting. Changes in VEGF expression were determined by real-time PCR. Effects of ENMD-1198 on cancer cell migration and invasion were evaluated in in vitro-assays. The growth-inhibitory effects of ENMD-1198 (200 mg/kg/day were determined in a subcutaneous tumor model (HUH-7. Results ENMD-1198 inhibited the phosphorylation of MAPK/Erk, PI-3K/Akt and FAK. Moreover, activation of HIF-1α and STAT3 was dramatically reduced by ENMD-1198, which resulted in lower VEGF mRNA expression (P In vivo, treatment with ENMD-1198 led to a significant reduction in tumor growth, tumor vascularization, and numbers of proliferating tumor cells (P Conclusion The novel microtubule destabilizing agent ENMD-1198 is suitable for inhibiting HIF-1α and STAT3 in human HCC cells and leads to reduced tumor growth and vascularization in vivo. Hence, inhibition of HIF-1α and STAT3 could prove valuable for therapy of hepatocellular carcinoma.

  9. Hepatocellular Carcinoma: The Role of Interventional Oncology

    Science.gov (United States)

    Donadon, Matteo; Solbiati, Luigi; Dawson, Laura; Barry, Aisling; Sapisochin, Gonzalo; Greig, Paul D; Shiina, Shuichiro; Fontana, Andrea; Torzilli, Guido

    2016-01-01

    Background Hepatocellular carcinoma (HCC) remains a major health issue because of its increasing incidence and because of the complexity of its management. In addition to the traditional potentially curative treatments, i.e., liver transplantation and surgical resection, other new and emerging local therapies have been applied with promising results. Summary Radiotherapy (RT) and interstitial treatments, such as radiofrequency ablation (RFA), microwave ablation (MWA), and irreversible electroporation (IRE), have recently opened new and interesting treatment scenarios for HCC and are associated with promising results in selected patients. Herein, we describe the emerging role of interventional oncology for the treatment of HCC and focus on the different Western and Eastern approaches. Key Messages Modern RT and modern interstitial therapies, such as RFA, MWA, and IRE, should be considered for inclusion in HCC therapy guidelines. PMID:27995086

  10. Hepatocellular carcinoma (HCC biomarkers in Colombia

    Directory of Open Access Journals (Sweden)

    María Cristina Navas

    2007-02-01

    Full Text Available

    The hepatocellular carcinoma (HCC account for 70 to 85% of primary liver cancer worldwide. SouthEast Asia and sub-Saharan Africa represent the areas with the highest incidence; instead Europe and North America correspond to low incidence areas. The data available for Latin American countries show a low incidence (<3.3/100.000 inhabitants in most of the countries including Colombia. The rate of incidence is <5.6/100.000 in Central America, Peru and Argentina and <10/100.000 in Chile and Brazil.

  11. Immunological landscape and immunotherapy of hepatocellular carcinoma.

    Science.gov (United States)

    Prieto, Jesús; Melero, Ignacio; Sangro, Bruno

    2015-12-01

    Advanced hepatocellular carcinoma (HCC) is a serious therapeutic challenge and targeted therapies only provide a modest benefit in terms of overall survival. Novel approaches are urgently needed for the treatment of this prevalent malignancy. Evidence demonstrating the antigenicity of tumour cells, the discovery that immune checkpoint molecules have an essential role in immune evasion of tumour cells, and the impressive clinical results achieved by blocking these inhibitory receptors, are revolutionizing cancer immunotherapy. Here, we review the data on HCC immunogenicity, the mechanisms for HCC immune subversion and the different immunotherapies that have been tested to treat HCC. Taking into account the multiplicity of hyperadditive immunosuppressive forces acting within the HCC microenvironment, a combinatorial approach is advised. Strategies include combinations of systemic immunomodulation and gene therapy, cell therapy or virotherapy.

  12. Stem cell research in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Chengyi SUN; Shi ZUO

    2008-01-01

    The traditional view that adult human liver tumors, mainly hepatocellular carcinoma (HCC), arise from mature cell types has been challenged in recent dec-ades. The results of several studies suggest that HCC can be derived from liver stem cells. There are four levels of cells in the liver stem cell lineage: hepatocytes, hepatic stem cells/oval cells, bone marrow stem cells and hepato-pancreas stem cells. However, whether HCC is resulted from the differentiation block of stem cells and, moreover, which liver stem cell lineage is the source cell of hepatocarcinogenesis remain controversial. In this review, we focus on the current status of liver stem cell research and their roles in carcinogenesis of HCC, in order to explore new approaches for stem cell therapy of HCC.

  13. Combined interventional therapies of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Jun Qian; Gan-Sheng Feng; Thomas Vogl

    2003-01-01

    Hepatocellular carcinoma (HCC) is one of the most commonmalignancies in the world, responsible for an estimated one million deaths annually. It has a poor prognosis due to its rapid infiltrating growth and complicating liver cirrhosis.Surgical resection, liver transplantation and cryosurgery are considered the best curative options, achieving a high rate of complete response, especially in patients with small HCC and good residual liver function. In nonsurgery, regional interventional therapies have led to a major breakthrough in the management of unresectable HCC, which include transarterial chemoembolization (TACE), percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave coagulation therapy (MCT), laser-induced thermotherapy (LITT), etc. As a result of the technical development of locoregional approaches for HCC during the recent decades,the range of combined interventional therapies has been continuously extended. Most combined multimodal interventional therapies reveal their enormous advantages as compared with any single therapeutic regimen alone,and play more important roles in treating unresectable HCC.

  14. Hepatocellular carcinoma:A comprehensive review

    Institute of Scientific and Technical Information of China (English)

    Lisa; P; Waller; Vrushak; Deshpande; Nikolaos; Pyrsopoulos

    2015-01-01

    Hepatocellular carcinoma(HCC) is rapidly becoming one of the most prevalent cancers worldwide. With a rising rate, it is a prominent source of mortality. Patients with advanced fibrosis, predominantly cirrhosis and hepatitis B are predisposed to developing HCC. Individuals withchronic hepatitis B and C infections are most commonly afflicted. Different therapeutic options, including liver resection, transplantation, systemic and local therapy, must be tailored to each patient. Liver transplantation offers leading results to achieve a cure. The Milan criteria is acknowledged as the model to classify the individuals that meet requirements to undergo transplantation. Mean survival remains suboptimal because of long waiting times and limited donor organ resources. Recent debates involve expansion of these criteria to create options for patients with HCC to increase overall survival.

  15. The effect of surgical excision combined with radioactive particles interstitial brachytherapy on serum indexes of patients with hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Zhi-Gang Dong; Li-Li Ma; Ya-Juan Li; Zhan-Hong Zhang

    2015-01-01

    Objective:To study the effect of surgical excision combined with radioactive particles interstitial brachytherapy on serum indexes of patients with hepatocellular carcinoma.Methods: 120 cases of patients with hepatocellular carcinoma received surgical treatment in our hospital were chosen and divided into combined treatment group and simple surgery group. Serum was collected after treatment and contents of miRNAs, hepatocellular carcinoma markers and Wnt signal molecules were detected.Results:(1) miRNAs: compared with serum miRNAs contents of simple surgery group, serum miR-1, miR-10a and miR-451 contents of combined treatment group were higher; miR-106b and miR-224 contents were lower; (2) hepatocellular carcinoma markers: compared with serum hepatocellular carcinoma marker contents of simple surgery group, serum AFP-L3, GP73, sB7-H3, AFU and Cat S contents of combined treatment group were all lower; (3) Wnt signal molecules: compared with serum Wnt signal molecule contents of simple surgery group, serum mRNA contents of Wnt,β-catenin, CyclinD1, c-myc, CD44v6 and VEGF of combined treatment group were lower.Conclusion:Surgical excision combined with radioactive particles interstitial brachytherapy is helpful to regulate miRNAs contents, reduce hepatocellular carcinoma marker contents and inhibit Wnt signal pathway function; it’s an ideal method in the treatment of hepatocellular carcinoma.

  16. Bacoside A downregulates matrix metalloproteinases 2 and 9 in DEN-induced hepatocellular carcinoma.

    Science.gov (United States)

    Janani, Panneerselvam; Sivakumari, Kanakarajan; Geetha, Arumugam; Yuvaraj, Sambandam; Parthasarathy, Chandrakesan

    2010-03-01

    Cancer metastasis is a complex multi-step process, responsible for a majority of cancer-related deaths by affecting the critical organs and causing complications in therapies. Hepatocellular carcinoma is a multi-factorial disease and is the third most common cause of cancer related mortality worldwide. Clinical and experimental studies have shown that MMP-2 and MMP-9 are involved in tumor invasion and metastases and their elevated expression has been associated with poor prognosis. Our recent studies showed a strong anti-oxidant and hepatoprotective effects of bacoside A (BA) against carcinogen. Nevertheless the effect of BA on the activities and expression of MMP-2 and MMP-9 during hepatocellular carcinoma is not yet recognized. Therefore, the present study was designed to assess the same. Results of gelatin zymography study showed that BA co-treatment significantly decreased the activities of MMP-2 and MMP-9, which is increased during hepatocellular carcinoma. Further immunoblot analysis showed decreased expression of MMP-2 and MMP-9 in rats co-treated with BA compared to DEN-induced hepatocellular carcinoma. Our results reveal that BA exerts its anti-metastatic effect against DEN-induced hepatocellular carcinoma by inhibiting the activities and expressions of MMP-2 and MMP-9.

  17. Salvage therapy for hepatocellular carcinoma with thalidomide

    Institute of Scientific and Technical Information of China (English)

    Tsang-En Wang; Chin-Roa Kao; Shee-Chan Lin; Wen-Hsiung Chang; Cheng-Hsin Chu; Johson Lin; Ruey-Kuen Hsieh

    2004-01-01

    AIM: To evaluate the clinical benefit of thalidomide in patients with advanced hepatocellular carcinoma (hepatoma).METHODS: From March 2000 to July 2002, patients who had advanced hepatocellular carcinoma and failed to or were unsuited for aggressive treatment, were enrolled and took thalidomide 150 to 300 mg/d. All cases were followed till April 2003. Data collection included viral hepatitis, grade of cirrhosis, total dosage of thalidomide, side effect, stage of hepatoma by Okuda and CLIP classification, and prognosis.The subjects were divided into A and B groups, depending on 5 000 mg dosage of thalidomide. Survival time of all cases and in the two subgroups was evaluated.RESULTS: Ninety-nine patients with hepatoma were enrolled,81 men and 18 females with median age 58±14.1 years.Eighty-six percent had viral hepatitis and one case was alcoholism. Hepatoma was diagnosed with histology, alphafetoprotein (aFP) >400 ng/mL, or image examination, there were 30, 33 and 36 cases respectively. At the time of thalidomide therapy, more than 81% had cirrhotic status.Twenty-two patients were in group A (<5 000 mg) with median survival time about 25 days, for 77 cases in group B (≥5 000 mg) the median survival time was about 109 days.Six subjects had partial response. Most adverse effects were skin rush, neuropathy, somnolence, and constipation.CONCLUSION: Several patients responded to thalidomide therapy. As a single drug therapy, thalidomide might not have good therapeutic effect for all cases, but a small ratio of patients had exciting response, the resistance or tumor escape would develop after long-term use. Up to now, no defined facts could be used to predict response. The effect of thalidomide on hepatoma might be associated with the dosage. As salvage therapy, thalidomide has its value.Combination or adjuvant therapy will be the next trial.

  18. Liver transplantation for hepatocellular carcinoma: an update.

    Science.gov (United States)

    Zarrinpar, Ali; Kaldas, Fady; Busuttil, Ronald W

    2011-06-01

    Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with multiple etiologies, high incidence, and high mortality. The standard surgical management for patients with HCC consists of locoregional ablation, surgical resection, or liver transplantation, depending on the background state of the liver. Eighty percent of patients initially presenting with HCC are unresectable, either due to the extent of tumor or the level of underlying hepatic dysfunction. While in patients with no evidence of cirrhosis and good hepatic function resection has been the surgical treatment of choice, it is contraindicated in patients with moderate to severe cirrhosis. Liver transplantation is the optimal surgical treatment. PubMed search of recent articles (from January 2000 to March 2011) was performed looking for relevant articles about hepatocellular carcinoma and its treatment. Additional articles were identified by evaluating references from selected articles. Here we review criteria for transplantation, the types, indications, and role of locoregional therapy in treating the cancer and in downstaging for possible later transplantation. We also summarize the contribution of immunosuppression and adjuvant chemotherapy in the management and prevention of HCC recurrence. Finally we discuss recent advances in imaging, tumor biology, and genomics as we delineate the remaining challenges for the diagnosis and treatment of this disease. Much can be improved in the diagnosis and treatment of HCC. A great challenge will be to improve patient selection to criteria based on tumor biology. Another will be to incorporate systemic agents post-operatively in patients at high risk for recurrence, paying close attention to efficacy and safety. The future direction of the effort in treating HCC will be to stimulate prospective trials, develop molecular imaging of lymphovascular invasion, to improve recipient selection, and to investigate biomarkers of tumor biology.

  19. BIOCHEMICAL NUTRITIONAL PROFILE OF LIVER CIRRHOSIS PATIENTS WITH HEPATOCELLULAR CARCINOMA

    Directory of Open Access Journals (Sweden)

    Gabriela Zanatta PORT

    2014-03-01

    Full Text Available Context Liver cirrhosis patients with hepatocellular carcinoma present nutritional alterations and metabolic disorders that negatively impact the prognosis. Objective The objective is to identify alterations in the metabolism of macro and micronutrients among liver cirrhosis patients with and without hepatocellular carcinoma and their relation to the Child-Turcote-Pugh score and Barcelona Clinic Liver Cancer staging. Methods Analytical transversal study, with 31 hepatocellular carcinoma patients and 48 liver cirrhosis patients. Laboratorial exams were carried out. The existence of an association between the biochemical parameters and the disease severity as well as the presence of hepatocellular carcinoma was assessed. Results The metabolic-nutritional profile of liver cirrhosis patients caused by the hepatitis C virus and hepatocellular carcinoma showed alterations, specifically the lipid (total cholesterol, HDL and triglycerides, protein (albumin, creatinine and uric acid, iron (transferrin, iron and ferritin saturation, hematocrit and hemoglobin, zinc and B12 vitamin profiles. There is a relation between nutritional biochemical markers and the Child-Turcote-Pugh, as well as Barcelona Clinic Liver Cancer staging. Conclusions Considering the existence of alterations in the metabolism of nutrients in liver cirrhosis patients with and without hepatocellular carcinoma, and also that conventional nutritional assessment methods present limitations for this population, the biochemical laboratorial exams are valid to complement the diagnosis of the nutritional state in a quick and practical manner.

  20. Experimental study of astaxanthin on inhibition of hepatocellular carcinoma growth%虾青素抗肝肿瘤生长的实验研究

    Institute of Scientific and Technical Information of China (English)

    陈立武; 曾维铨

    2012-01-01

    Objective To assess the effects of astaxanthin on inhibition of hepatocellular carcinoma growth and to investi -gate the possible mechanism. Methods Hepa 1-6 tumor-bearing mice model was established, and 24 mice were divided into control group, low dose group (10 mg/kg), middle dose group (30 mg/kg) and high dose group (60 mg/kg) according to the different treatments concentration of astaxanthin, each group had 6 mice. The impaction of astaxanthin on tumor growth was observed, and the impaction of astaxanthin on lymphocyte proliferation and cytotoxicity in tumor-bearing mice were analyzed. Results After treatment for 20 d, the tumor volume of control group was larger than that of low dose group, mid -die dose group and high dose group, the differences were statistically significant (P < 0.05 or P < 0.01). Astaxanthin could promote the multiplication of splenocyte, the splenocyte number of control group was compared with middle and high dose groups, the differences were statistically significant (P < 0.05). Astaxanthin could enhance the killer ability of lymphocyte, which had a does-dependent tendency. Conclusion Astaxanthin treatment can increase the level of host immunity, which has a good efficacy of anti-tumors.%目的 探讨虾青素抗肝肿瘤生长的作用及其可能的作用机制.方法 建立Hepa 1-6 荷瘤小鼠模型,根据虾青素处理浓度不同将24 只小鼠分为对照组、低剂量组(10 mg/kg)、中剂量组(30 mg/kg)、高剂量组(60 mg/kg),每组各6 只,观察虾青素对肿瘤生长的影响,并检测虾青素对荷瘤鼠淋巴细胞增殖和杀伤的影响.结果 处理后第20 天,对照组肿瘤体积均大于低、中、高剂量组,差异均有统计学意义(P < 0.05 或P < 0.01);虾青素可促进宿主脾细胞的增殖,对照组脾细胞数与中、高剂量组比较,差异有统计学意义(P < 0.05);虾青素可增强淋巴细胞对肿瘤的杀伤能力,且呈剂量依赖趋势.结论 虾青素能够增强宿主免疫水

  1. Immunosupression in liver transplant for hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Juan Carlos Restrepo Restrepo

    2007-02-01

    Full Text Available

    The hepatocellular carcinoma (HCC has turned into a frequent indication for liver transplant. The reports of different series indicate that it represents at least 12% of all liver transplants in Europe. But what kind of inmunosuppression is better in these patients is an unanswered question. Our intension with this review is to give basic information to define which would be the best immunosuppression alternative. There is enough information on the relationship between immunosuppression and cancer, as it is seen in states of primary immunodeficiency or infection with the Human Immunodeficiency virus (HIV. The immune system offers a state of permanent guard to avoid the arousal of neoplasic diseases in immunocompetent patients and from this point of view it has been seen that in immunosuppressed patients there is an association with this condition and the development of lymphoproliferative disorders, which can range from reversible diseases (polyclonal proliferation of B type lymphocytes to the development of a lymphoma and other types of tumors, like the ones observed in skin, genital region or oropharynx. Colon tumors and breast tumors have not been associated with immunosuppression. Immunosuppressive medication takes part in a different manner in the development of tumors, it has been said that steroids that are associated with some tumors, especially those regarding skin, paradoxically have a protective role in the development of lymph tissue tumors.

    It has been said about Azathioprine and Mycophenolate mofetil (MMF that its immunosuppressive effect is an antiproliferative type of immunosuppression, inhibiting the synthesis of purinic nucleotides, especially in lymphocytes. Azathioprine has been involved in the development of hepatic tumors, especially in the era previous

  2. Paraneoplastic alopecia associated with hepatocellular carcinoma in a cat.

    Science.gov (United States)

    Marconato, Laura; Albanese, Francesco; Viacava, Paolo; Marchetti, Veronica; Abramo, Francesca

    2007-08-01

    A 15-year-old spayed female domestic shorthair cat presented with alopecia associated with hepatocellular carcinoma. Clinical signs, which had commenced 6 months previously, included loss of appetite, loss of weight, and depression. As reported by the owner, the cat developed alopecia a week before referral. The hair loss was localized to the ventral aspect of the thorax and abdomen, medial aspect of front and hind limbs, and ventral aspect of the tail, and was associated with histological features consistent with paraneoplastic alopecia. At necropsy, multiple hepatic nodules were observed, and subsequent histopathological investigation showed cords and sheets of hepatocyte-like neoplastic cells positive for the hepatocyte marker (Hep Par 1), thereby demonstrating the hepatocellular origin of the tumour, which was diagnosed as a hepatocellular carcinoma. This is the first report of feline paraneoplastic alopecia associated with hepatocellular carcinoma confirmed by the Hep Par 1 marker.

  3. BRAIN METASTASIS FROM HEPATOCELLULAR CARCINOMA: A RARE CASE

    Directory of Open Access Journals (Sweden)

    A. Kh. Bekyashev

    2012-01-01

    Full Text Available Hepatocellular carcinoma ranks 5th in prevalence and 3rd in cancer mortality worldwide. The prognosis of this disease is very poor: the 5-year survival rate was not more than 3–5%. Metastases generally occur in the lung, in the lymph nodes of the abdomen, chest, and neck, in the vertebrae, kidneys, and adrenals. The cases of brain metastasis from hepatocellular cancer are very rare. Overall, the prognosis is very poor for patients with brain metastases from hepatocellular carcinoma. Nevertheless, solitary brain metastases and good hepatic function are favorable survival criteria; thus, the treatment of this group of patients may lead to their better survival. The paper describes a clinical case of brain metastasis from hepatocellular carcinoma in a patient receiving the combination treatment involving neurosurgical treatment and targeted therapy. 

  4. Radiofrequency (thermal) ablation versus no intervention or other interventions for hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Weis, Sebastian; Franke, Annegret; Mössner, Joachim

    2013-01-01

    Hepatocellular carcinoma is the fifth most common cancer worldwide. Percutaneous interventional therapies, such as radiofrequency (thermal) ablation (RFA), have been developed for early hepatocellular carcinoma. RFA competes with other interventional techniques such as percutaneous ethanol...

  5. Antiviral therapy for prevention of hepatocellular carcinoma in chronic hepatitis C

    DEFF Research Database (Denmark)

    Kimer, Nina; Dahl, Emilie Kristine; Gluud, Lise Lotte;

    2012-01-01

    To determine whether antiviral therapy reduces the risk of developing hepatocellular carcinoma (HCC) in chronic hepatitis C.......To determine whether antiviral therapy reduces the risk of developing hepatocellular carcinoma (HCC) in chronic hepatitis C....

  6. Inhibition of hydrogen peroxide signaling by 4-hydroxynonenal due to differential regulation of Akt1 and Akt2 contributes to decreases in cell survival and proliferation in hepatocellular carcinoma cells.

    Science.gov (United States)

    Shearn, Colin T; Reigan, Philip; Petersen, Dennis R

    2012-07-01

    Dysregulation of cell signaling by electrophiles such as 4-hydroxynonenal (4-HNE) is a key component in the pathogenesis of chronic inflammatory liver disease. Another consequence of inflammation is the perpetuation of oxidative damage by the production of reactive oxidative species such as hydrogen peroxide. Previously, we have demonstrated Akt2 as a direct target of 4-HNE in hepatocellular carcinoma cells. In the present study, we used the hepatocellular carcinoma cell line HepG2 as model to understand the combinatorial effects of 4-HNE and hydrogen peroxide. We demonstrate that 4-HNE inhibits hydrogen peroxide-mediated phosphorylation of Akt1 but not Akt2. Pretreatment of HepG2 cells with 4-HNE prevented hydrogen peroxide stimulation of Akt-dependent phosphorylation of downstream targets and intracellular Akt activity compared with untreated control cells. Using biotin hydrazide capture, it was confirmed that 4-HNE treatment resulted in carbonylation of Akt1, which was not observed in untreated control cells. Using a synthetic GSK3α/β peptide as a substrate, treatment of recombinant human myristoylated Akt1 (rAkt1) with 20 or 40 μΜ 4-HNE inhibited rAkt1 activity by 29 and 60%, respectively. We further demonstrate that 4-HNE activates Erk via a PI3 kinase and PP2A-dependent mechanism leading to increased Jnk phosphorylation. At higher concentrations, 4-HNE decreased both cell survival and proliferation as evidenced by MTT assays and EdU incorporation as well as decreased expression of cyclin D1 and β-catenin, an effect only moderately increased by the addition of hydrogen peroxide. The ability of 4-HNE to exert combinatorial effects on Erk, Jnk, and Akt-dependent cell survival pathways provides additional insight into the mechanisms of cellular damage associated with chronic inflammation.

  7. CYCLOOXYGENASE-2 AND HEPATOCELLULAR CARCINOMA: THE PROTEOMICS OF ASSOCIATION

    Directory of Open Access Journals (Sweden)

    Jaya Gandhi

    2011-12-01

    Full Text Available Hepatocellular carcinoma represents one of the most common malignancies worldwide with a rising incidence in western countries. Chronic inflammation is recognised as a threat factor for cancer progression. Cyclooxygenase-2 is the major mediator of inflammation. Various studies on Cox-2 suggest its possible association with HCC differentiation. Sufficient genetic and pharmacologic evidences implicate its crucial role in neoplasia and it is also now clear that Cox-2 plays a crucial role in tumor progression. Cox-2 overexpression is associated with maintaining tumor microenvironment and has crucial implication for angiogenesis. Cox-2 operates in multifactorial fashion. Cox-2 selective inhibition has been reported as a successful tool in suppressing angiogenesis and metastasis. The pharmacological suppression of Cox-2 represents a bright future as a therapeutic tool for treatment of various malignancies. This review is an attempt to discuss the critical issue of overexpression of Cox-2 and its role in the development of HCC in particular and cancer in general.

  8. Thalidomide induces complete remission of advanced hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Cheng-Hung Chien

    2014-06-01

    Full Text Available Hepatocellular carcinoma (HCC is one of the most prevalent human cancers in the world, but its prognosis is extremely poor. HCC is considered a hypervascular tumor. Thalidomide, which has been known to inhibit growth factor-induced neovascularization, is a convenient alternative to target therapy such as sorafenib. We report a 65-year-old male patient with alcoholic liver cirrhosis that was diagnosed having multiple HCCs during surveillance. The patient was assessed as inoperable and unsuited for transhepatic arterial chemoembolization or systemic chemotherapy. After discussing the therapeutic alternatives, he decided to receive low-dose thalidomide (100 mg daily therapy. Fortunately, follow-up liver biochemical tests, serum α-fetoprotein level, and dynamic computed tomography showed complete remission of the HCCs 4.5 months after thalidomide treatment and this was documented for more than 22 months without evidence of tumor recurrence.

  9. Nano-pulse stimulation (NPS) ablate tumors and inhibit lung metastasis on both canine spontaneous osteosarcoma and murine transplanted hepatocellular carcinoma with high metastatic potential.

    Science.gov (United States)

    Chen, Xinhua; Chen, Yiling; Jiang, Jianwen; Wu, Liming; Yin, Shengyong; Miao, Xudong; Swanson, Robert J; Zheng, Shusen

    2017-07-04

    Nanosecond pulsed electric field (nsPEF), which is also termed as nano-pulse stimulation (NPS), has the potential of stimulating immune responses toward cancer cells. The current study investigates its local and systemic antitumor efficacy in vivo in late stage tumors with lung metastasis. The 12 canines with spontaneous osteosarcomas and 12 nude mice transplanted with human hepatocellular carcinoma were divided randomly and were given NPS treatment, surgery or no treatment control. Nanosecond pulsed electric field was delivered with puncture electrodes at 40 kV/cm with 500 pulses at 1 Hz. The survival time, tumor volume, serum alkaline phosphatase (ALP), joint capsule damage and lung metastasis were followed up. The efficacy was compared with control. Nanosecond pulsed electric field reduced primary tumor volume and extended the survival significantly compared to the control group (Plung metastasis without joint deformity or thermal damage were also observed. Locally applied nanosecond pulsed electric field is a novel non-thermal ablation method. It can ablate the primary tumor and decrease lung metastasis as a palliative therapy for late stage tumor.

  10. Endobronchial metastasis from hepatocellular carcinoma – a case description with literature review

    OpenAIRE

    Szumera-Ciećkiewicz, Anna; Olszewski, Włodzimierz T.; Piech, Krzysztof; Głogowski, Maciej; Prochorec-Sobieszek, Monika

    2013-01-01

    Endobronchial metastases from hepatocellular carcinoma are very rare. Up to date, no more than 7 cases were reported. The authors present a case of 20-year old female with metastatic hepatocellular carcinoma to superior lobar bronchus. Examination of cytological and small biopsy specimens obtained from bronchoscopy revealed characteristic microscopic features and immunohistochemical profile of hepatocellular carcinoma.

  11. Endobronchial metastasis from hepatocellular carcinoma – a case description with literature review

    Science.gov (United States)

    Szumera-Ciećkiewicz, Anna; Olszewski, Włodzimierz T; Piech, Krzysztof; Głogowski, Maciej; Prochorec-Sobieszek, Monika

    2013-01-01

    Endobronchial metastases from hepatocellular carcinoma are very rare. Up to date, no more than 7 cases were reported. The authors present a case of 20-year old female with metastatic hepatocellular carcinoma to superior lobar bronchus. Examination of cytological and small biopsy specimens obtained from bronchoscopy revealed characteristic microscopic features and immunohistochemical profile of hepatocellular carcinoma. PMID:24040462

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  7. Tumor vaccine against recurrence of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Bao-Gang Peng; Li-Jiang Liang; Qiang He; Ming Kuang; Jia-Ming Lia; Ming-De Lu; Jie-Fu Huang

    2005-01-01

    AIM: To investigate the effects of autologous tumor vaccine on recurrence of hepatocellular carcinoma (HCC).METHODS: Sixty patients with HCC who had undergone curative resection, were randomly divided into HCC vaccine group and control group. Three vaccinations at 2-wk intervals were performed after curative hepatic resection. Delayedtype- hypersensitivity (DTH) test was performed before and after vaccination. Primary endpoints were the time of recurrence.RESULTS: Four patients in control group and 6 patients in HCC vaccine group were withdrawn from the study. The vaccine containing human autologous HCC fragments showed no essential adverse effect in a phase Ⅱ clinical trial and 17 of 24 patients developed a DTH response against the fragments. Three of 17 DTH-positive response patients and 5 of 7 DTH- negative response patients had recurrences after curative resection. After the operation,1-, 2- and 3-year recurrence rates of HCC vaccine groupwere 16.7%, 29.2% and 33.3%, respectively. But, 1-, 2- and3-year recurrence rates of the control group were 30.8%,53.8% and 61.5%, respectively. The time before the first recurrence in the vaccinated patients was significantly longer than that in the control patients (P<0.05).CONCLUSION: Autologous tumor vaccine is of promise in decreasing recurrence of human HCC.

  8. Senescence and immortality in hepatocellular carcinoma.

    Science.gov (United States)

    Ozturk, Mehmet; Arslan-Ergul, Ayca; Bagislar, Sevgi; Senturk, Serif; Yuzugullu, Haluk

    2009-12-01

    Cellular senescence is a process leading to terminal growth arrest with characteristic morphological features. This process is mediated by telomere-dependent, oncogene-induced and ROS-induced pathways, but persistent DNA damage is the most common cause. Senescence arrest is mediated by p16(INK4a)- and p21(Cip1)-dependent pathways both leading to retinoblastoma protein (pRb) activation. p53 plays a relay role between DNA damage sensing and p21(Cip1) activation. pRb arrests the cell cycle by recruiting proliferation genes to facultative heterochromatin for permanent silencing. Replicative senescence that occurs in hepatocytes in culture and in liver cirrhosis is associated with lack of telomerase activity and results in telomere shortening. Hepatocellular carcinoma (HCC) cells display inactivating mutations of p53 and epigenetic silencing of p16(INK4a). Moreover, they re-express telomerase reverse transcriptase required for telomere maintenance. Thus, senescence bypass and cellular immortality is likely to contribute significantly to HCC development. Oncogene-induced senescence in premalignant lesions and reversible immortality of cancer cells including HCC offer new potentials for tumor prevention and treatment.

  9. Protocol of Interventional Treatment for Hepatocellular Carcinoma

    Institute of Scientific and Technical Information of China (English)

    CHENXiaoming; LUOPengfei; LINHuahuan; SHAOPeijian; ZHOUZejian; FULi

    2005-01-01

    Objective: To establish a reasonable protocol for interventional treatment of hepatocellular carcinoma (HCC). Methods: The data of 1000 HCC patients treated by different kinds of interventional treatments were reviewed with their results of biochemistry, imaging, pathology and survival rate cvaluated.The values as well as the pros and cons of these various kinds of interventional treatments were compared in order to find an optimal protocol. Results: Segmental-transcatheter oil chemoembolization (S-TOCE) could more effectively eradicate the tumor yet inflicting less damage on the noncancerous hepatic tissue and giving much higher survival rate than the conventional transcatheter oil chemoembolization (C-TOCE).Precutaneous ethanol injection (PEI) in combination with chemoembolization could eliminate the residual tumor and significantly increase the survival rate without damaging the noncancerous hepatic tissue. The living quality or survival rate could be improved by choosing different ways of iuterventional treatments to cut down the complications. Conclusion: The selection of different interventional treatments should be done according to the size and type of HCC. Active management is indicated for different complications presenting along with HCC.

  10. Management of recurrent hepatocellular carcinoma afterliver transplant

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Hepatocellular carcinoma (HCC) is the leading cause ofdeaths in patients with hepatitis B or C, and its incidencehas increased considerably over the past decade and is stillon the rise. Liver transplantation (LT) provides the bestchance of cure for patients with HCC and liver cirrhosis.With the implementation of the MELD exception systemfor patients with HCC waitlisted for LT, the number ofrecipients of LT is increasing, so is the number of patientswho have recurrence of HCC after LT. Treatments forintrahepatic recurrence after transplantation and afterother kinds of surgery are more or less the same, butlong-term cure of posttransplant recurrence is rarelyseen as it is a "systemic" disease. Nonetheless, surgicalresection has been shown to be effective in prolongingpatient survival despite the technical difficulty in resectinggraft livers. Besides surgical resection, different kindsof treatment are also in use, including transarterialchemoembolization, radiofrequency ablation, highintensityfocused ultrasound ablation, and stereotacticbody radiation therapy. Targeted therapy and modulationof immunosuppressants are also adopted to treat thedeadly disease.

  11. Aflatoxins, hepatocellular carcinoma and public health.

    Science.gov (United States)

    Magnussen, Arvin; Parsi, Mansour A

    2013-03-14

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide, primarily affecting populations in the developing countries. Aflatoxin, a food contaminant produced by the fungi Aspergillus flavus and Aspergillus parasiticus, is a known human carcinogen that has been shown to be a causative agent in the pathogenesis of HCC. Aflatoxin can affect a wide range of food commodities including corns, oilseeds, spices, and tree nuts as well as milk, meat, and dried fruit. Many factors affect the growth of Aspergillus fungi and the level of aflatoxin contamination in food. Drought stress is one of the factors that increase susceptibility of plants to Aspergillus and thus aflatoxin contamination. A recent drought is thought to be responsible for finding of trace amounts of aflatoxin in some of the corn harvested in the United States. Although it's too soon to know whether aflatoxin will be a significant problem, since United States is the world's largest corn producer and exporter, this has raised alarm bells. Strict regulations and testing of finished foods and feeds in the United States should prevent a major health scare, and prevent human exposure to deleterious levels of aflatoxin. Unfortunately, such regulations and testing are not in place in many countries. The purpose of this editorial is to summarize the current knowledge on association of aflatoxin and HCC, encourage future research and draw attention to this global public health issue.

  12. Comprehensive sequential interventional therapy for hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    ZHANG Liang; FAN Wei-jun; HUANG Jin-hua; LI Chuan-xing; ZHAO Ming; WANG Li-gang; TANG Tian

    2009-01-01

    Background Since the 1980s, various approaches to interventional therapy have been developed, with the development and achievement of medical imaging technology. This study aimed to evaluate the effectiveness of comprehensive sequential interventional therapy especially personal therapeutic plan in 53 radical cure patients with hepatocellular carcinoma (HCC).Methods From January 2003 to January 2005, a total of 203 patients with HCC received sequential interventional treatment in our hospital. Fifty-three patients achieved radical cure outcomes. Those patients were treated with transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), or high intensity focused ultrasound (HIFU), sequentially and in combination depending on their clinical and pathological features. PET-CT was used to evaluate, assess, and guide treatment.Results Based on the imaging and serological data, all the patients had a personal therapeutic plan. The longest follow-up time was 24 months, the shortest was 6 months, and mean survival time was 16.5 months.Conclusion Comprehensive sequential interventional therapy especially personal therapeutic plan for HCC play roles in interventional treatment of HCC in middle or advanced stage.

  13. Hepatocellular carcinoma in patients with autoimmune hepatitis

    Institute of Scientific and Technical Information of China (English)

    Andreas Teufel; Arndt Weinmann; Catherine Centner; Anja Piendl; Peter R Galle; Ansgar W Lohse; Stephan Kanzler

    2009-01-01

    AIM: To evaluate and confirm the low incidence of hepatocellular carcinoma (HCC) in patients with autoimmune hepatitis (AIH). At present only very few cases of HCC in patients with AIH and definite exclusion of chronic viral hepatitis have been published,suggesting that HCC due to AIH is rare. METHODS: In order to further investigate the incidence of HCC in patients with AIH, we reviewed our large cohort of 278 patients with AIH. RESULTS: Eighty-nine patients (32%) were diagnosed with liver cirrhosis, a preneoplastic condition for HCC. We studied a total of 431 patient years of cirrhosis in these patients, an average 4.8 years per patient. During this period none of the patients of our own study cohort developed HCC. However, three patients with HCC due to AIH associated liver cirrhosis were referred to our department for further treatment of HCC. In all three patients chronic viral hepatitis was excluded. CONCLUSION: We conclude that HCC may under rare circumstances develop due to chronic AIH dependent liver cirrhosis. Compared to other causes of liver cirrhosis such as chronic viral hepatitis, alcohol, or hemochromatosis, the incidence of HCC is significantly lower. Pathophysiological differences between AIH and chronic viral hepatitis responsible for differences in the incidence of HCC are yet to be further characterized and may lead to new therapeutic concepts in prevention and treatment of liver cancer.

  14. Hepatocellular carcinoma: a systems biology perspective

    Directory of Open Access Journals (Sweden)

    Lorenza Alice D'alessandro

    2013-02-01

    Full Text Available Hepatocellular carcinomas (HCC have different etiology and heterogenic genomic alterations lead to high complexity. The molecular features of HCC have largely been studied by gene expression and proteome profiling focusing on the correlations between the expression of specific markers and clinical data. Integration of the increasing amounts of data in databases has facilitated the link of genomic and proteomic profiles of HCC to disease state and clinical outcome. Despite the current knowledge, specific molecular markers remain to be identified and new strategies are required to establish novel targeted therapies. In the last years, mathematical models reconstructing gene and protein networks based on experimental data of HCC have been developed providing powerful tools to predict candidate interactions and potential targets for therapy. Furthermore, the combination of dynamic and logical mathematical models with quantitative data allows detailed mechanistic insights into system properties. To address effects at the organ level, mathematical models reconstructing the three-dimensional organization of liver lobules were developed. In the future, integration of different modeling approaches capturing the effects at the cellular up to the organ level is required to address the complex properties of HCC and to enable the discovery of new targets for HCC prevention or treatment.

  15. Status of hepatocellular carcinoma in Gulf region.

    Science.gov (United States)

    Rasul, Kakil Ibrahim; Al-Azawi, Safaa H; Chandra, Prem; Abou-Alfa, Ghassan K; Knuth, Alexander

    2013-12-01

    Hepatocellular carcinoma (HCC) has a unique geographic distribution that is likely to be determined by specific etiologic factors. There is a distinctive difference in sex and age related occurrence of disease. In the Gulf region, there are contradicting data on the prevalence and death rates due to HCC. In this review we highlight some aspects of HCC specific to the Gulf region. A retrospective analysis of 150 patient's data is presented, including demographic, epidemiological, aetiological disease status assessment with child Pugh criteria, modes of treatment and treatment related outcome. Hepatitis C virus (HCV) infection was the most common (45%) documented etiology, similar to Western European countries, followed by hepatitis B virus (HBV) infection in 27% of cases, alcoholic liver disease only in six patients (4%). Child-Pugh assessment was A in 33%, B in 37% and C in 30% of observed patients. Surgery (liver resection or transplantation) was performed in 12% and local ablation in 5% of cases. The others were treated by chemo-embolization in 17% and by systemic therapy with sorafenib in 13% of patients. Nearly half of the patients (53%) were in advanced stages and received palliative treatment. To improve the outcome of treatment in HCC patients in the Gulf region, an effective and strategic screening program must be implemented for early diagnosis and treatment to improve the outcome of this mostly fatal disease.

  16. Association between hepatitis C and hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Luis Jesuino de Oliveira Andrade

    2009-01-01

    Full Text Available Hepatocellular carcinoma (HCC is the fifth most common cancer, the third most common cause for cancer death in the world, a major cause of death in patients with chronic hepatitis C virus infection, and responsible for approximately one million deaths each year. Overwhelming lines of epidemiological evidence have indicated that persistent infection with hepatitis C virus (HCV is a major risk for the development of HCC. The incidence of HCC is expected to increase in the next two decades, largely due to hepatitis C infection and secondary cirrhosis, and detection of HCC at an early stage is critical for a favorable clinical outcome. Potential preventive strategies in the development of HCC are being recognized. The natural history of HCC is highly variable and the clinical management choices for HCC can be complex, hence patient assessment and treatment planning have to take the severity of the nonmalignant liver disease into account. This review summarizes the inter-relationship between HCV and liver carcinogenesis.

  17. Association Between Hepatitis C and Hepatocellular Carcinoma

    Science.gov (United States)

    de Oliveria Andrade, Luis Jesuino; D'Oliveira, Argemiro; Melo, Rosangela Carvalho; De Souza, Emmanuel Conrado; Costa Silva, Carolina Alves; Paraná, Raymundo

    2009-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common cancer, the third most common cause for cancer death in the world, a major cause of death in patients with chronic hepatitis C virus infection, and responsible for approximately one million deaths each year. Overwhelming lines of epidemiological evidence have indicated that persistent infection with hepatitis C virus (HCV) is a major risk for the development of HCC. The incidence of HCC is expected to increase in the next two decades, largely due to hepatitis C infection and secondary cirrhosis, and detection of HCC at an early stage is critical for a favorable clinical outcome. Potential preventive strategies in the development of HCC are being recognized. The natural history of HCC is highly variable and the clinical management choices for HCC can be complex, hence patient assessment and treatment planning have to take the severity of the nonmalignant liver disease into account. This review summarizes the inter-relationship between HCV and liver carcinogenesis. PMID:20300384

  18. Activins and activin antagonists in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Alev Deli; Emanuel Kreidl; Stefan Santifaller; Barbara Trotter; Katja Seir; Walter Berger; Rolf Schulte-Hermann; Chantal Rodgarkia-Dara; Michael Grusch

    2008-01-01

    In many parts of the world hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood. There is increasing evidence that activins, which are members of the transforming growth factor β (TGFβ) superfamily of growth and differentiation factors, could play important roles in liver carcinogenesis. Activins are disulphide-linked homo-or heterodimers formed from four different β subunits termed βA, βB, βC, and βE, respectively. Activin A, the dimer of two βA subunits, is critically involved in the regulation of cell growth, apoptosis, and tissue architecture in the liver, while the hepatic function of other activins is largely unexplored so far. Negative regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG, and at the cell membrane antagonistic co-receptors like Cripto or BAMBI. Additionally, in the intracellular space inhibitory Smads can modulate and control activin activity. Accumulating data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation, fibrosis and development of cancer. The current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis.

  19. Management of hepatocellular carcinoma in the elderly

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Mean age of hepatocellular carcinoma (HCC) patients hasbeen progressively increasing over the last decades andageing of these patients is becoming a real challenge inevery day clinical practice. Unfortunately, internationalguidelines on HCC management do not address thisproblem exhaustively and do not provide any specific recommendation. We carried out a literature search inMEDLINE database for studies reporting on epidemiology,clinical characteristics and treatment outcome of HCCin elderly patients. Available data seem to indicatethat in elderly patients the outcome of HCC is mostlyinfluenced by liver function and tumor stage rather thanby age and the latter should not influence treatmentallocation. Age is not a risk for resection and olderpatients with resectable HCC and good liver functioncould gain benefit from surgery. Mild comorbiditiesdo not seem a contraindication for surgery in agedpatients. Conversely, major resection in elderly, evenwhen performed in experienced high-volume centres,should be avoided. Both percutaneous ablation andtransarterial chemoembolization are not contraindicatedin aged patients and safety profile of these proceduresis acceptable. Sorafenib is a viable option for advancedHCC in elderly provided that a careful evaluation ofconcomitant comorbidities, particularly cardiovascularones, is taken into account. Available data seem tosuggest that in either elderly and younger, treatment isa main predictor of outcome. Consequently, a nihilisticattitude of physicians towards under- or no-treatment ofaged patients should not be longer justified.

  20. Portal vein embolization for hepatocellular carcinoma.

    Science.gov (United States)

    Shindoh, Junichi; D Tzeng, Ching-Wei; Vauthey, Jean-Nicolas

    2012-11-01

    Portal vein embolization (PVE) improves the safety of major hepatectomy through hypertrophy of the future liver remnant (FLR), atrophy of the liver volume to be resected, and improvement in patient selection. Because most patients with hepatocellular carcinoma (HCC) have liver parenchymal injury due to underlying viral hepatitis or alcoholic liver fibrosis/cirrhosis, indication of PVE is relatively complex and sequential procedures, including transarterial chemoembolization, are required to maximize the effect of PVE as well as to minimize tumor progression due to increased arterial flow after PVE. PVE is currently indicated for patients with relatively well-preserved hepatic function [Child-Pugh A and indocyanine green tolerance test (ICG-R15) 40% is the minimal requirement for patients with chronic hepatitis or cirrhosis, and further strict criteria (FLR volume >50%) have been recommended for patients with marginal liver functional reserve (ICG-R15, 10-20%). Recent clinical results have suggested that PVE can be safely performed in patients with HCC and that it contributes to improved survival after major hepatectomy.

  1. Obesity, insulin resistance, NASH and hepatocellular carcinoma.

    Science.gov (United States)

    Yu, Jun; Shen, Jiayun; Sun, Ting Ting; Zhang, Xiang; Wong, Nathalie

    2013-12-01

    Epidemiological and clinical data have clearly demonstrated that non-alcoholic steatohepatitis (NASH) predisposes risk to the development of hepatocellular carcinoma (HCC). NASH is the liver manifestation of metabolic syndrome, which constellates obesity, insulin resistance and dyslipidemia. Although the percentage of patients diagnosed annually with NASH-associated HCC is still relatively low, this number signifies a large population due to the rapidly increasing incidence of obesity and diabetes globally. Fundamental studies on lipid storage, regulation of adipose factors, inflammatory cytokine recruitments and oxidative stress have provided insights into NASH as well as metabolic syndrome. Recent evidence also indicates the significant role of genetic factors in contributing to the pathogenesis of NASH and induced hepatic malignancy. In this review, we attempt to collate current research on NASH biology that lead to our understandings on how metabolic disorders may intersect with cancer development. We also discuss study models that have supported discoveries of molecular and cellular defects, and offered a perspective on therapeutic developments. These studies have collectively increased our knowledge on the complex signaling pathways involved in NASH and cancer, and provided the foundation for improved clinical management of patients with metabolic diseases. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Nonalcoholic fatty liver disease and hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    LI Liangping

    2016-03-01

    Full Text Available As the etiology of hepatocellular carcinoma (HCC has been changing, the incidence of HCC related to nonalcoholic fatty liver disease (NAFLD is gradually increasing in developed countries in Europe and America and some countries in Asia. This article introduces the close association between NAFLD and HCC, risk factors, clinicopathological features, and prevention and screening, and points out that although the incidence of NAFLD is not as high as that of hepatitis B- or hepatitis C-related HCC, there are a large absolute number of NAFLD patients, especially the high-risk patients with diabetes and obesity, or liver fibrosis/cirrhosis, due to a huge base number of NAFLD patients. NAFLD-related HCC is commonly seen in the elderly with various comorbidities and a poor prognosis. This article also points out that the prevention should focus on the effective treatment of NAFLD. The strict screening of high-risk population is the strategy for the diagnosis of early-stage HCC. At present, the sensitivity of alpha-fetoprotein is relatively low, and imaging examinations including computed tomography are the main screening methods; however, there are no measures for early warning of NAFLD-related HCC.

  3. Mast cells and human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Fabio Grizzi; Barbara Franceschini; Maurizio Chiriva-Internati; Young Liu; Paul L. Hermonat; Nicola Dioguardi

    2003-01-01

    AIM: To investigate the density of mast cells (MCs) in human hepatocellular carcinoma (HCC), and to determine whether the MCs density has any correlations with histopathological grading, staging or some baseline patient characteristics.METHODS: Tissue sections of 22 primary HCCs were histochemically stained with toluidine blue, in order to be able to quantify the MCs in and around the neoplasm using a computer-assisted image analysis system. HCC was staged and graded by two independent pathologists. To identify the sinusoidal capillarisation of each specimen 3μm thick sections were histochemically stained with sirius red, and semi-quantitatively evaluated by two independent observers. The data were statistically analysed using Spearman′s correlation and Student′s t-test when appropriate.RESULTS: MCs density did not correlate with the age or sex of the patients, the serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, or the stage or grade of the HCC. No significant differences were found between the MCs density of the patients with and without hepatitis C virus infection, but they were significantly higher in the specimens showing marked sinusoidal capillarisation.CONCLUSION: The lack of any significant correlation between MCs density and the stage or grade of the neoplastic lesions suggests that there is no causal relationship between MCs recruitment and HCC. However, as capillarisation proceeds concurrently with arterial blood supply during hepatocarcinogenesis, MCs may be considered of primary importance in the transition from sinusoidal to capillary-type endothelial cells and the HCC growth.

  4. The new research on tumor suppressor gene in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    JI Yu-bin; YANG Hai-fan; YU Lei; PANG lin-lin; LI Hai-jiao; LIU Guang-da

    2008-01-01

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death in the world. The carcinogenesis of HCC is multifactorial, multifunctional and multistage. Tumor suppressor gene therapy is one of the strategies, it is mainly used to make use of tumor suppressor gene groups which can inhibit the cell growth, to prevent the expression of oncogenes or to resume the function of anti-oncogenes. But so far, there is not a particular gene to be a main tumor suppressor gene in HCC. Therefore, it is necessary to study on the new anti-oncogenes to explain pathogenesis of liver cancer and seek for the newly effective target to carry on liver cancer gene therapy. PTEN (phosphatase and tensin homolog deleted on chromosome ten) was discovered as a tumor suppressor gene. It functions as a protein tyrosine phosphatase and as a lipid phosphatase. As a lipid phosphatase, PTEN antagonizes PI3K/Akt signaling by dephosphorylating the D3 position of the inositol ring of phosphatidylinositol 3, 4, 5-trisphosphate(PIP3), to generate phosphatidylinositol-4, 5,- biphosphate(PIP2). On the other hand, as a protein tyrosine phosphatase, PTEN can dephosphorylate itself, focal adhesion kinase (FAK) and the platelet derived growth factor receptor, involves in the migration, adhension of cells. Many researches have been testified that there is a higher frequency of negative expression of PTEN protein in hepatocellular carcinoma, the negative correlation between expression of PTEN gene and differential grade, clinic stage of HCC indicated that in activation of PTEN gene maybe a late incidence in the development of hepatocellular carcinoma and may play an important role in the genesis and development of some hepatocellular carcinoma. KLF6, a member of Krupple-like gene family, a ubiquitously expressed zinc finger transcription factor, has an important role in regulating cell growth and differentiation. Several experiments have been proved that the genetic events of tumor

  5. miR-200a targets Gelsolin: A novel mechanism regulating secretion of microvesicles in hepatocellular carcinoma cells.

    Science.gov (United States)

    Xu, Ya; Zhang, Yanfen; Wang, Lujing; Zhao, Ruiqi; Qiao, Yu; Han, Dong; Sun, Qian; Dong, Nazhen; Liu, Yicong; Wu, Dantong; Zhang, Xuemei; Huang, Ning; Ma, Ning; Zhao, Weiming; Liu, Yanhong; Gao, Xu

    2017-05-01

    Microvesicle biogenesis is a highly regulated process. Aberrant release of microvesicles from cancer cells have been associated with their invasiveness and prognosis. However, the mechanism of aberrant release remains poorly understood. Herein, we found that hepatocellular carcinoma cells shed more microvesicles than normal hepatocytes and miR-200a were shown to inhibit the release of microvesicles in hepatocellular carcinoma cells. Then, we confirmed that miR-200a might target Gelsolin and change cytoskeleton to regulate microvesicles secretion. Further miR-200a may inhibit the proliferation of adjacent cells by inhibiting the release of microvesicles. Collectively, our findings indicate that miR-200a regulated the microvesicle biogenesis involved in the hepatocellular carcinoma progression.

  6. HGF, MET, and matrix-related proteases in hepatocellular carcinoma, fibrolamellar variant, cirrhotic and normal liver.

    Science.gov (United States)

    Schoedel, Karen E; Tyner, Valerie Zajac; Kim, Tae-Hyoung; Michalopoulos, George K; Mars, Wendy M

    2003-01-01

    Fibrolamellar variant is an uncommon subcategory of hepatocellular carcinoma with a better prognostic outcome. Proteinases and growth factors that are involved in the remodeling of extracellular matrix may influence the behavior of cancers. To determine whether these factors contribute to the distinct etiologies of fibrolamellar hepatocellular carcinoma and traditional hepatocellular carcinoma, we assayed hepatocyte growth factor, the hepatocyte growth factor receptor, and two hepatocyte growth factor activators, hepatocyte growth factor activator and urokinase-type plasminogen activator, in hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, cirrhotic liver and normal liver. In addition, we examined the urokinase-type plasminogen activator receptor, the type 1 plasminogen activator inhibitor, plasmin, fibrinogen, and the type IV matrix metalloproteinases. Eighteen hepatocellular carcinomas and 11 fibrolamellar hepatocellular carcinomas were obtained as paraffin embedded sections from the University of Pittsburgh Department of Pathology. Frozen tissues from a subset of cases (9 hepatocellular carcinomas, 4 fibrolamellar hepatocellular carcinomas, 12 cirrhotic livers and 2 normal livers) were also available for analysis. Antibodies against urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, hepatocyte growth factor and hepatocyte growth factor receptor were used to analyze immunoperoxidase stained slides from the paraffin blocks. Western blot analyses using antibodies against hepatocyte growth factor, hepatocyte growth factor receptor, phosphotyrosine, hepatocyte growth factor activator, urokinase-type plasminogen activator receptor, urokinase-type plasminogen activator, plasminogen activator inhibitor-1, fibrinogen and plasmin were performed on membrane-enriched fractions from the frozen tissue, as was collagen zymography for matrix metalloproteinase-2 and matrix metalloproteinase-9. The most notable findings are as

  7. Multiple ectopic hepatocellular carcinomas in the pancreas: A case report.

    Science.gov (United States)

    Li, Zhigui; Wu, Xiaoting; Wen, Tianfu; Li, Chuan; Peng, Wen

    2017-07-01

    Ectopic liver tissue can develop at various sites near the liver. Ectopic hepatocellular carcinomas (HCCs) arising from ectopic liver tissue have a rare clinical incidence. A very rare case has been observed to have metastasis after operation. We report an extremely rare case with multiple masses which were identified in the head and body of the pancreas. Ectopic hepatocellular carcinomas. The masses were removed by surgical resection. Histopathological analysis showed that both masses were ectopic HCC. The patient was still alive and did not have metastasis and relapse. The literature review for this rare case is also presented to highlight the risk of ectopic HCC and good prognosis of operation for ectopic HCC.

  8. Hep par-1: a novel immunohistochemical marker for differentiating hepatocellular carcinoma from metastatic carcinoma.

    Science.gov (United States)

    Hanif, Razia; Mansoor, Samina

    2014-03-01

    To evaluate the diagnostic utility of Hep par-1 in differentiating hepatocellular carcinoma from metastatic carcinoma taking histopathology as a gold standard. Comparative cross-sectional study. Pathology Department, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, from April 2007 to February 2008. Hep par-1 immunohistochemical stain was performed on 60 cases of liver carcinoma, 30 cases each of metastatic and hepatocellular carcinoma. Information regarding patient age, gender, sign and symptoms, radiographic findings, histological grade of tumour, and expression of Hep par-1 on hepatocellular and metastatic carcinoma were recorded on proforma sheet. Sensitivity, specificity, positive and negative predictive values, and accuracy of Hep par-1 were calculated using the formulas. Hep par-1 expression was noted in 25 out of 30 cases of hepatocellular carcinoma (83%). Out of 30 cases of metastatic carcinoma, only one case expressed staining in Hep par-1 is a reliable immunohistochemical marker for cases of hepatocellular carcinoma (HCC). It can be used along with other markers in morphologically difficult cases when differential diagnosis lies between poorly differentiated HCC and metastatic carcinoma of liver.

  9. Helicobacter infection in hepatocellular carcinoma tissue

    Institute of Scientific and Technical Information of China (English)

    Shi-Ying Xuan; Ning Li; Xin Qiang; Rong-Rong Zhou; Yong-Xin Shi; Wen-Jie Jiang

    2006-01-01

    AIM: To investigate whether Helicobacter species (Helicobacter spp.) could be detected in hepatocellular carcinoma (HCC) tissue.METHODS: Liver samples from 28 patients with hepatocellular carcinoma (HCC) diagnosed by histopathology were studied. Twenty-two patients with other liver diseases (5 with liver trauma, 7 with cavernous liver hemangioma, 6 with liver cyst and 4 with hepatolithiasis), 25 patients with gastric cancer, 15 with colonic cancer and 15 with myoma of uterus served as controls. Two piceces of biopsy were obtained from each patient. One was cultured for Helicobacter spp. and extraction of DNA, the other was prepared for scanning electron microscopy (SEM) and in situ hybridization. The samples were cultured on Columbia agar plates with microaerobic techniques. Helicobacter spp. in biopsy from the studied subjects was detected by polymerase chain reaction (PCR) with Helicobacter spp. 16S rRNA primers. Amplified products were identified by Southern hybridization and sequenced further. Besides, other genes (vacA, cagA) specific for Helicobacter pylori (H pylori) were also detected by PCR. Helicobacter spp. in biopsies was observed by SEM. Transmission electron microscopy (TEM) was performed to identify the cultured positive Helicobacter spp. The presence of Helicobacter spp. was detected by in situ hybridization to confirm the type of Helicobacter.RESULTS: The positive rate of Helicobacter cultured in HCC and gastric cancer tissue was 10.7% (3/28) and 24%(6/25), respectively. Helicobacter microorganisms were identified further by typical appearance on Gram staining, positive urease test and characteristic colony morphology on TEM. The bacterium was observed in adjacent hepatocytes of the two HCC samples by SEM.The number of cocci was greater than that of bacilli. The bacterium was also found in four gastric cancer samples.PCR showed that the positive rate of HCC and gastric cancer samples was 60.7% and 72% respectively, while the controls were negative

  10. Targeting cancer stem cells in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    He AR

    2014-12-01

    Full Text Available Aiwu Ruth He,1 Daniel C Smith,1 Lopa Mishra2 1Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 2Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Abstract: The poor outcome of patients with hepatocellular carcinoma (HCC is attributed to recurrence of the disease after curative treatment and the resistance of HCC cells to conventional chemotherapy, which may be explained partly by the function of liver cancer stem cells (CSCs. Liver CSCs have emerged as an important therapeutic target against HCC. Numerous surface markers for liver CSCs have been identified, and include CD133, CD90, CD44, CD13, and epithelial cell adhesion molecules. These surface markers serve not only as tools for identifying and isolating liver CSCs but also as therapeutic targets for eradicating these cells. In studies of animal models and large-scale genomic analyses of human HCC samples, many signaling pathways observed in normal stem cells have been found to be altered in liver CSCs, which accounts for the stemness and aggressive behavior of these cells. Antibodies and small molecule inhibitors targeting the signaling pathways have been evaluated at different levels of preclinical and clinical development. Another strategy is to promote the differentiation of liver CSCs to less aggressive HCC that is sensitive to conventional chemotherapy. Disruption of the tumor niche essential for liver CSC homeostasis has become a novel strategy in cancer treatment. To overcome the challenges in developing treatment for liver CSCs, more research into the genetic makeup of patient tumors that respond to treatment may lead to more effective therapy. Standardization of HCC CSC tumor markers would be helpful for measuring the CSC response to these agents. Herein, we review the current strategies for developing treatment to eradicate liver CSCs and to improve the outcome for patients with

  11. Stereotactic Body Radiotherapy for Primary Hepatocellular Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Andolino, David L., E-mail: dandolin@iupui.edu [Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN (United States); Johnson, Cynthia S. [Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN (United States); Maluccio, Mary [Department of Surgery, Indiana University School of Medicine, Indianapolis, IN (United States); Kwo, Paul [Department of Medicine, Indiana University School of Medicine, Indianapolis, IN (United States); Tector, A. Joseph [Department of Surgery, Indiana University School of Medicine, Indianapolis, IN (United States); Zook, Jennifer; Johnstone, Peter A.S.; Cardenes, Higinia R. [Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN (United States)

    2011-11-15

    Purpose: To evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) for the treatment of primary hepatocellular carcinoma (HCC). Methods and Materials: From 2005 to 2009, 60 patients with liver-confined HCC were treated with SBRT at the Indiana University Simon Cancer Center: 36 Child-Turcotte-Pugh (CTP) Class A and 24 CTP Class B. The median number of fractions, dose per fraction, and total dose, was 3, 14 Gy, and 44 Gy, respectively, for those with CTP Class A cirrhosis and 5, 8 Gy, and 40 Gy, respectively, for those with CTP Class B. Treatment was delivered via 6 to 12 beams and in nearly all cases was prescribed to the 80% isodose line. The records of all patients were reviewed, and treatment response was scored according to Response Evaluation Criteria in Solid Tumors v1.1. Toxicity was graded according to the Common Terminology Criteria for Adverse Events v4.0. Local control (LC), time to progression (TTP), progression-free survival (PFS), and overall survival (OS) were calculated according to the method of Kaplan and Meier. Results: The median follow-up time was 27 months, and the median tumor diameter was 3.2 cm. The 2-year LC, PFS, and OS were 90%, 48%, and 67%, respectively, with median TTP of 47.8 months. Subsequently, 23 patients underwent transplant, with a median time to transplant of 7 months. There were no {>=}Grade 3 nonhematologic toxicities. Thirteen percent of patients experienced an increase in hematologic/hepatic dysfunction greater than 1 grade, and 20% experienced progression in CTP class within 3 months of treatment. Conclusions: SBRT is a safe, effective, noninvasive option for patients with HCC {<=}6 cm. As such, SBRT should be considered when bridging to transplant or as definitive therapy for those ineligible for transplant.

  12. Outcome of Hepatectomy for Huge Hepatocellular Carcinoma.

    Science.gov (United States)

    Jo, Sungho

    2011-05-01

    In spite of the recent improved results of hepatectomy for huge hepatocellular carcinomas (HCC), the prognosis of patients with huge HCCs is still poor compared to that of patients with small HCCs. This study was performed to compare the results of hepatectomy between patients with huge HCCs and those with small HCCs, to identify the prognostic factors in patients with huge HCCs, and to determine the preoperative selection criteria. We retrospectively analyzed 51 patients who underwent hepatectomy, between July 1994 and February 2009 at Dankook University Hospital. Patients with HCC≥10 cm were classified in large (L) group and others were classified in small (S) group. The clinicopathological features, operative procedures, and postoperative outcome were compared between both groups and various prognostic factors were investigated in group L. Eleven patients were classified in group L. Tumor size, vascular invasion, and tumor stage were higher in group L. Postoperative morbidity was higher in group L, but mortality was not different between the groups. Disease-free survivals were significantly lower in group L than in group S (36.4%, and 24.2% vs. 72.0%, and 44.0% for 1- and 3-year), but overall survival rates were similar in both groups (45.5%, and 15.2% in group L vs. 60.3%, and 41.3% in group S for 3- and 5-year). Presence of satellite nodules was the only prognostic factor in multivariate analysis after surgery for huge HCC. Regardless of tumor size, huge HCCs deserve consideration for surgery in patients with preserved liver function. Furthermore, the effect of surgery could be maximized with appropriate selection criteria, such as huge HCC without satellite nodules.

  13. Loss of fragile histidine triad protein in human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Po Zhao; Xin Song; Yuan-Yuan Nin; Ya-Li Lu; Xiang-Hong Li

    2003-01-01

    AIM: To investigate the expression of fragile histidine triad (FHIT) gene protein, Fhit, which is recently thought to be a candidate tumor suppressor. Abnormal expression of fragile histidine triad has been found in a variety of human cancers,but little is known about its expression in human hepatocellular carcinogenesis and evolution.METHODS: Sections of 83 primary human hepatocellular carcionoma with corresponding para-neoplastic liver tissue and 10 normal liver tissue were evaluated immunohistochemically for Fhit protein expression.RESULTS: All normal liver tissue and para-neoplastic liver tissue showed a strong expression of Fhit, whereas 50 of 83(65.0 %) carcinomas showed a marked loss or absence of Fhit expression. The differences of Fhit expression between carcinoma and normal or para-neoplastic liver tissue werehighly significant (P=0.000). The proportion of carcinomas with reduced Fhit expression showed an increasing trend (a) with decreasing differentiation or higher histological grade (P=0.219); (b) in tumors with higher clinical stage Ⅲ and ⅣV (91.3 %, P=0.000), compared with tumors with lower stage Ⅰ and Ⅱ (27.6 %); and (c) in cancers with bigger tumor size (>50 mm) (75.0 %, P=0.017), compared withsmaller tumor size (≤ 50 mm). CONCLUSION: FHIT inactivation seems to be both an earlyand a later event, associated with carcinogenesis andprogression to more aggressive hepatocellular carcinomas.Thus, evaluation of Fhit expression by immunohistochemistryin hepatocellular carcinoma may provide important diagnosticand prognostic information in clinical application.

  14. SERUM LEPTIN LEVENS AND HEPATOCELLULAR CARCINOMA: REVIEW ARTICLE.

    Science.gov (United States)

    Andrighetto, Luiza Vitelo; Poziomyck, Aline Kirjner

    2016-01-01

    Hepatocellular carcinoma is one of the most frequent types of malignant tumors in the world. There is growing evidence of the relationship between it development and obesity. The mechanism that links obesity to cancer is still not fully understood; however, it is essential to the understanding the adipose tissue in metabolic changes related to obesity and hepatocellular carcinoma. To review the influence of serum leptin levels in patients with hepatocelular carcinoma. Systematic review of the literature based on the methodology of the Cochrane Institute. The search for articles was in the database: Science Direct, Scielo, Medline, Lilacs e Pubmed. The key words used were hepatocellular carcinoma, leptin, adipokine. After evaluation of individual studies, were selected seven studies. The results previously studied are still inconsistent and contradictory, and leptin can be effectively involved in the occurrence and development of hepatocellular carcinoma. Therefore, it is necessary to develop prospective, well-designed and conducted focusing on the role and specific mechanisms of this hormone in patients with hepatocellular carcinoma, so that new correlations can be properly supported. O carcinoma hepatocelular é um dos tipos mais frequentes de tumores malignos no mundo. Há crescentes evidências da relação entre o seu desenvolvimento e a obesidade. O mecanismo que os relaciona ainda não é completamente entendido. Entretanto é essencial a compreensão do tecido adiposo nas alterações metabólicas relacionadas à obesidade e ao câncer. Revisar a influência dos níveis séricos de leptina em pacientes com carcinoma hepatocelular. Trata-se de revisão bibliográfica baseada na metodologia do Instituto Cochrane; a busca de dados foi realizada na base de dados Science Direct, Scielo, Medline, Lilacs e Pubmed, empregando as seguintes descritores: hepatocellular carcinoma, leptin, adipokine. Após avaliação individual dos artigos selecionaram-se sete estudos

  15. Abnormal plasma prothrombin (PIVKA-II) levels in hepatocellular carcinoma.

    Science.gov (United States)

    Kawaguchi, Y

    1989-05-01

    The concentration of abnormal prothrombin, or the protein induced by vitamin K absence or antagonist II (PIVKA-II) in 102 patients with hepatic disorders was measured by an enzyme immunoassay method. The concentration of PIVKA-II in the plasma was elevated in 11 out of 18 patients with hepatocellular carcinoma and also in a patient with hepatoblastoma. There was no correlation between serum alpha-fetoprotein and plasma PIVKA-II levels. The PIVKA-II level was normal in 11 patients who had metastatic carcinoma or cholangiocellular carcinoma. Moreover, benign diseases of the liver did not cause an elevation in PIVKA-II. PIVKA-II might be an useful marker of hepatocellular carcinoma because, like alpha-fetoprotein, its level changes in close relation to the effects of treatment.

  16. Reduced expression of TANGO in colon and hepatocellular carcinomas.

    Science.gov (United States)

    Arndt, Stephanie; Bosserhoff, Anja K

    2007-10-01

    The TANGO gene was originally identified as a new family member of the MIA gene family. The gene codes for a 14-kDa protein of so far unknown function. Recently, we identified TANGO as a tumor suppressor in malignant melanoma. In this study we evaluated TANGO transcription in different colon and hepatocellular carcinoma cell lines and tissue samples, to analyze whether loss of TANGO expression is a more general process in tumor development. TANGO was down-regulated or lost in all hepatocellular and colon cell lines compared to primary human hepatocytes or normal colon epithelial cells, respectively, and in most of the tumor samples compared to non-tumorous tissue. These results were confirmed in situ by immunohistochemistry on paraffin-embedded sections of colon and hepatocellular tumors. Functional assays with exogenous TANGO treatment of colon and hepatoma cell lines revealed reduced motility and invasion capacity. Our studies present for the first time the down-regulation of TANGO in colon and hepatocellular carcinoma and provide the first indications for a tumor suppressor role of the TANGO gene in human colon and hepatocellular carcinoma. Thus, functional relevant loss of TANGO expression may contribute to general tumor development and progression, and may provide a new target for therapeutic strategies.

  17. Differentially expressed genes between solitary large hepatocellular carcinoma and nodular hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Lian-Yue Yang; Wei Wang; Ji-Xiang Peng; Jie-Quan Yang; Gen-Wen Huang

    2004-01-01

    AIM: To study the difference in gene expression between solitary large hepatocellular carcinoma (SLHCC) and nodular hepatocellular carcinoma (NHCC).METHODS: Polymerase chain reaction (PCR) products of 8464 human genes were spotted on a chip in array. DNAs were then fixed on a glass plate. Total RNA was isolated from freshly excised human SLHCC (n=7) and NHCC (n=15)tissues, and was reversely transcribed to cDNAs with the incorporation of fluorescent dUTP for preparation of hybridization probes. The mixed probes were then hybridized to the cDNA microarray. After highly stringent washing,cDNA microarray was scanned for the fluorescent signals to display the difference between the two kinds of HCC. In addition, the expression of RhoC and protocadherin LKC was also detected with the reverse transcriptase polymerase chain reaction (RT-PCR) method.RESULTS: Among the 8 464 human genes, 668 (7.89%)genes were expressed differentially at the mRNA levels between SLHCC and NHCC. Three hundred and fifty five (4.19%) genes, including protocadherin LKC, were upregulated, whereas 313 (3.70%) genes, including RhoC,were down-regulated. The mRNA expression levels of RhoC and protocadherin LKCwere confirmed by RT-PCR. Analysis of differentially expressed genes confirmed that our molecular data obtained by cDNA microarray were consistent with the published biochemical and clinical observations of SLHCC and NHCC.CONCLUSION: cDNA microarray is an effective technique in screening the difference in gene expression between SLHCC and NHCC. Many of these differentially expressed genes are involved in the invasion and metastasis of HCC.Further analysis of these genes will help to understand the different molecular mechanisms of SLHCC and NHCC.

  18. Can non-selective beta-blockers prevent hepatocellular carcinoma in patients with cirrhosis?

    DEFF Research Database (Denmark)

    Thiele, Maja; Wiest, Reiner; Gluud, Lise Lotte

    2013-01-01

    Hepatocellular carcinoma is the main liver-related cause of death in patients with compensated cirrhosis. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. We propose that non-selective beta-blockers decrease the incidence and growth of hepatocellular...... carcinoma via a reduction of the inflammatory load from the gut to the liver and inhibition of angiogenesis. Due to their effect on the portal pressure, non-selective beta-blockers are used for prevention of esophageal variceal bleeding. Recently, non-hemodynamic effects of beta-blockers have received...... reduce hepatic inflammation. Blockage of β-adrenoceptors also decrease angiogenesis by inhibition of vascular endothelial growth factors. Because gut-derived inflammation and neo-angiogenesis are important in hepatic carcinogenesis, non-selective beta-blockers can potentially reduce the development...

  19. The repressive effect of miR-148a on TGF beta-SMADs signal pathway is involved in the glabridin-induced inhibition of the cancer stem cells-like properties in hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Fei Jiang

    Full Text Available Hepatocellular carcinoma (HCC is the third leading cause of cancer-related mortality worldwide. Current standard practices for treatment of HCC are less than satisfactory because of cancer stem cells (CSCs-mediated post-surgical recurrence. For this reason, targeting the CSCs or the cancer cells with CSCs-like properties has become a new approach for the treatment of HCC. GLA exhibits anti-tumor effects in that it attenuates the proliferation, migration, invasion, and angiogenesis of human cancer cells. However, the functions of GLA in the regulation of CSCs-like properties in HCC cells, and the molecular mechanisms underlying in remain obscure. Here we found that GLA attenuated the CSCs-like properties by the microRNA-148a (miR-148a-mediated inhibition of transforming growth factor beta (TGF-β/SMAD2 signal pathway in HCC cell lines (HepG2, Huh-7, and MHCC97H. Indeed, GLA inhibited the activations/expressions of both TGFβ-induced and the endogenous SMAD2. Further, GLA improved the expression of miR-148a in a dose/time-dependent manner. MiR-148a, which targeted the SMAD2-3'UTR, decreased the expression and function of SMAD2. Knockdown of miR-148a abolished the GLA-induced inhibition of TGF-β/SMAD2 signal pathway and the CSCs-like properties in HCC cells. Our study found a novel mechanism that GLA inhibits the CSCs-like properties of HCC cells by miR-148a-mediated inhibition of TGF-β/SMAD2 signal pathway, which may help to identify potential targets for the therapies of HCC.

  20. Correlation of exon 3 β-catenin mutations with glutamine synthetase staining patterns in hepatocellular adenoma and hepatocellular carcinoma.

    Science.gov (United States)

    Hale, Gillian; Liu, Xinxin; Hu, Junjie; Xu, Zhong; Che, Li; Solomon, David; Tsokos, Christos; Shafizadeh, Nafis; Chen, Xin; Gill, Ryan; Kakar, Sanjay

    2016-11-01

    The current clinical practice is based on the assumption of strong correlation between diffuse glutamine synthetase expression and β-catenin activation in hepatocellular adenoma and hepatocellular carcinoma. This high correlation is based on limited data and may represent an oversimplification as glutamine synthetase staining patterns show wide variability in clinical practice. Standardized criteria for interpreting diverse glutamine synthetase patterns, and the association between each pattern and β-catenin mutations is not clearly established. This study examines the correlation between glutamine synthetase staining patterns and β-catenin mutations in 15 typical hepatocellular adenomas, 5 atypical hepatocellular neoplasms and 60 hepatocellular carcinomas. Glutamine synthetase staining was classified into one of the three patterns: (a) diffuse homogeneous: moderate-to-strong cytoplasmic staining in >90% of lesional cells, without a map-like pattern, (b) diffuse heterogeneous: moderate-to-strong staining in 50-90% of lesional cells, without a map-like pattern, and (c) patchy: moderate-to-strong staining in glutamine synthetase staining (homogeneous or heterogeneous), an exon 3 β-catenin mutation was detected in 33% (2/6) of typical hepatocellular adenoma, 75% (3/4) of atypical hepatocellular neoplasm and 17% (8/47) of hepatocellular carcinomas. An exon 3 mutation was also observed in 15% (2/13) of hepatocellular carcinomas with patchy glutamine synthetase staining. The results show a modest correlation between diffuse glutamine synthetase immunostaining and exon 3 β-catenin mutations in hepatocellular adenoma and hepatocellular carcinoma with discrepancy rates >50% in both hepatocellular adenoma and hepatocellular carcinoma. The interpretation of β-catenin activation based on glutamine synthetase staining should be performed with caution, and the undetermined significance of various glutamine synthetase patterns should be highlighted in pathology reports.

  1. Growing role of CD40 ligand gene transfer therapy in the management of systemic malignancies besides hepatocellular carcinomas

    Institute of Scientific and Technical Information of China (English)

    Shailendra KAPOOR

    2009-01-01

    @@ The article "Cationic liposome-mediated trans-fection of CD40 ligand gene inhibits hepatic tumor growth of hepatocellular carcinoma in mice" [doi:10. 1631/jzus.B0820178] by Jiang et a1.(2009) in a recent issue of the Journal of Zhejiang University SCIENCE B was highly thought provoking. The authors have clearly demonstrated the efficacy of CD40 ligand gene therapy in inhibiting the growth of hepatocellu-lar carcinomas. The findings of Jiang et al.(2009) are highly important as they further support and cor-roborate the rapidly expanding role of CD40 ligand gene therapy in the management of systemic malig-nancies besides hepatocellular carcinomas.

  2. The Correlation between Gene Polymorphism and Hepatocellular Carcinoma

    Institute of Scientific and Technical Information of China (English)

    Zhao-Chun Chi; Chang-Xin Geng; Quan-Jiang Dong

    2013-01-01

    The association of gene polymorphism and susceptibility to hepatocellular carcinoma (HCC) has been widely studied in recent years. Gene mutations are closely related to HCC. Understanding and measuring the gene mutations are useful to reduce the incidence of HCC and improve its prognosis.

  3. Hepatocellular carcinoma: perfusion quantification with dynamic contrast-enhanced MRI

    NARCIS (Netherlands)

    Taouli, B.; Johnson, R.S.; Hajdu, C.H.; Oei, M.T.H.; Merad, M.; Yee, H.; Rusinek, H.

    2013-01-01

    The objective of our study was to report our initial experience with dynamic contrast-enhanced MRI (DCE-MRI) for perfusion quantification of hepatocellular carcinoma (HCC) and surrounding liver.DCE-MRI of the liver was prospectively performed on 31 patients with HCC (male-female ratio, 26:5; mean ag

  4. Cerebral lipiodol embolism following transcatheter arterial chemoembolization for hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Cerebral lipiodol embolism (CLE) is an extremely rare complication of transcatheter arterial chemoembolization for hepatocellular carcinoma (HCC). The authors present a case of CLE that occurred after the second hepatic arterial chemoembolization for HCC, and attempt to introduce several plausible mechanisms of CLE, after reporting the clinical and radiological findings and reviewing the medical literature.

  5. Metabolomic profiles of hepatocellular carcinoma in a European prospective cohort

    NARCIS (Netherlands)

    Fages, Anne; Duarte-Salles, Talita; Stepien, Magdalena; Ferrari, Pietro; Fedirko, Veronika; Pontoizeau, Clement; Trichopoulou, Antonia; Aleksandrova, Krasimira; Tjonneland, Anne; Olsen, Anja; Clavel-Chapelon, Franoise; Boutron-Ruault, Marie-Christine; Severi, Gianluca; Kaaks, Rudolf; Kuhn, Tilman; Floegel, Anna; Boeing, Heiner; Lagiou, Pagona; Bamia, Christina; Trichopoulos, Dimitrios; Palli, Domenico; Pala, Valeria; Panico, Salvatore; Tumino, Rosario; Vineis, Paolo; Bueno-de-Mesquita, H. Bas; Peeters, Petra H.; Weiderpass, Elisabete; Agudo, Antonio; Molina-Montes, Esther; Maria Huerta, Jose; Ardanaz, Eva; Dorronsoro, Miren; Sjoberg, Klas; Ohlsson, Bodil; Khaw, Kay-Tee; Wareham, Nick; Travis, Ruth C.; Schmidt, Julie A.; Cross, Amanda; Gunter, Marc; Riboli, Elio; Scalbert, Augustin; Romieu, Isabelle; Elena-Herrmann, Benedicte; Jenab, Mazda

    2015-01-01

    Background: Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is difficult to diagnose and has limited treatment options with a low survival rate. Aside from a few key risk factors, such as hepatitis, high alcohol consumption, smoking, obesity, and diabetes, there is incomplet

  6. Metabolomic profiles of hepatocellular carcinoma in a European prospective cohort

    NARCIS (Netherlands)

    Fages, Anne; Duarte-Salles, Talita; Stepien, Magdalena; Ferrari, Pietro; Fedirko, Veronika; Pontoizeau, Clement; Trichopoulou, Antonia; Aleksandrova, Krasimira; Tjonneland, Anne; Olsen, Anja; Clavel-Chapelon, Franoise; Boutron-Ruault, Marie-Christine; Severi, Gianluca; Kaaks, Rudolf; Kuhn, Tilman; Floegel, Anna; Boeing, Heiner; Lagiou, Pagona; Bamia, Christina; Trichopoulos, Dimitrios; Palli, Domenico; Pala, Valeria; Panico, Salvatore; Tumino, Rosario; Vineis, Paolo; Bueno-de-Mesquita, H. Bas; Peeters, Petra H.; Weiderpass, Elisabete; Agudo, Antonio; Molina-Montes, Esther; Maria Huerta, Jose; Ardanaz, Eva; Dorronsoro, Miren; Sjoberg, Klas; Ohlsson, Bodil; Khaw, Kay-Tee; Wareham, Nick; Travis, Ruth C.; Schmidt, Julie A.; Cross, Amanda; Gunter, Marc; Riboli, Elio; Scalbert, Augustin; Romieu, Isabelle; Elena-Herrmann, Benedicte; Jenab, Mazda

    2015-01-01

    Background: Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is difficult to diagnose and has limited treatment options with a low survival rate. Aside from a few key risk factors, such as hepatitis, high alcohol consumption, smoking, obesity, and diabetes, there is

  7. HCCNet: an integrated network database of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Bing He; Xiaojie Qiu; Peng Li; Lishan Wang; QiLv; TieliuShi

    2010-01-01

    @@ Dear Editor, As a complex disease, the development and progression of hepatocellular carcinoma (HCC) involves the interactions of multiple proteins, genes and miRNAs in various biological pathways, and it has been extensively studied with different high-throughput techniques.

  8. Peanut butter consumption and hepatocellular carcinoma in Sudan

    NARCIS (Netherlands)

    El Hadi Omer, R.

    2001-01-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world with 80% of cases occurring in developing countries in sub-Saharan regions in Africa, South-East Asia and China. The cancer is highly fatal and survival is generally less than 1 year from diagnosis. Clinical records suggest

  9. Chronic hepatitis C presenting with a diagnosis of hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Hallager, Sofie; Weis, Nina

    2014-01-01

    Chronic hepatitis C (CHC) affects around 16,000 individuals in Denmark of whom about 50% are diagnosed. In the presence of CHC and cirrhosis the annual risk of hepatocellular carcinoma (HCC) is 1-5%. We report on two patients who presented with disseminated HCC at the time of CHC diagnosis...

  10. Peanut butter consumption and hepatocellular carcinoma in Sudan

    NARCIS (Netherlands)

    Hadi Omer, El R.

    2001-01-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world with 80% of cases occurring in developing countries in sub-Saharan regions in Africa, South-East Asia and China. The cancer is highly fatal and survival is generally less than 1 year from diagnosis. Clinical records

  11. Application of Proteomics to the Study of Hepatocellular Carcinoma and Some Related Diseases

    Institute of Scientific and Technical Information of China (English)

    Yueguo Li; Xin Geng; Weiming Zhang

    2005-01-01

    Hepatocellular carcinoma is a malignant tumor causing one of the highest death rates in the world. Viral hepatitis, hepatic fibrosis and hepatocirrhosis etc. Are some of the most important causes of hepatocellular carcinoma. With the advent of the post-genomic age, studying carcinoma and some related diseases using the developing technology of proteomics has become a major focus of researchers. This article is a review of the application of proteomics to study hepatocellular carcinoma and some related diseases.

  12. Screening for hepatocellular carcinoma by Egyptian physicians

    Institute of Scientific and Technical Information of China (English)

    Sahar; M; Hassany; Ehab; F; Abdou; Moustafa; Mohamed; El; Taher; Afaf; Adel; Abdeltwab; Hubert; E; Blum

    2015-01-01

    AIM: To assess the practice of Egyptian physicians in screening patients for hepatocellular carcinoma(HCC). METHODS: The study included 154 physicians from all over Egypt caring for patients at risk for HCC. The study was based on a questionnaire with 20 items. Each questionnaire consisted of two parts:(1) personal information regarding the physician(name, age, specialty and type of health care setting); and(2) professional experience in the care of patients at risk for HCC development(screening, knowledge about the cause and natural course of liver diseases and HCC risk). RESULTS: Sixty-eight percent of doctors with an MD degree, 48% of doctors with a master degree or a diploma and 40% of doctors with a Bachelor of Medicine, Bachelor of Surgery certificate considered the hepatitis C virus(HCV) genotype as risk factor for HCC development(P < 0.05). Ninety percent of physicians specialized in tropical medicine, internal medicine or gastroenterology and 67% of physicians in other specialties advise patients to undergo screening for HCV and hepatitis B virus infection as well as liver cirrhosis(P < 0.05). Eighty-six percent of doctors in University Hospitals and 69% of Ministry of Health(MOH) doctors consider HCV infection as the leading cause of HCC in Egypt(P < 0.05). Seventy-two percent of doctors with an MD degree, 55% of doctors with a master degree or a diploma, 56% of doctors with an MBBCH certificate, 74% of doctors in University Hospitals and 46% of MOH hospital doctors consider abdominal ultrasonography as the most important investigation in HCC screening(P < 0.05). Sixty-five percent of physicians in tropical medicine, internal medicine or gastroenterology and 37% of physicians in other specialties recommend as HCC screening interval of 3 mo(P < 0.05). Seventy-one percent of doctors with an MD degree, 50% of doctors with a master degree or diploma and 60% of doctors with an MBBCH certificate follow the same recommendation.CONCLUSION: In Egypt, physicians

  13. Hepatocellular carcinoma in Asia: Prevention strategy andplanning

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    AIM To review all of epidemiological and etiologicalaspects of hepatocellular carcinoma (HCC) and examinedthe prevention of this disease in Asia.METHODS: We conducted a systematic reviewaccording to the PRISMA guidelines. We were chosenarticles that published previously, from PubMed(MEDLINE), the Cochrane database and Scopus. Thekey words used in this research were as follows: HCCin Asia and the way of prevention of this disease, withno language limitations. We selected those paperspublished before 2014 that we considered to be mostimportant and appropriate. All relevant articles wereaccessed in full text and all relevant materials wasevaluated and reviewed.RESULTS: More than 70% of all new cases of livercancer were diagnosed in Asia, a region that 75% of allthose chronically infected with hepatitis B virus (HBV)in the world. Chronic HBV infection is the main causeof HCC in Asia, where the virus is endemic and verticaltransmissionis common. Japan, Saudi Arabia, Egyptand Pakistan are exception because of high prevalenceof HCV infection in these regions. The prevalence of thiscancer is high in Eastern and South-Eastern Asia, ButMiddle Eastern countries are characterized as moderateprevalence rate of HCC region and Central Asia andsome part of Middle Eastern countries are known as lowprevalence rate of HCC. In addition of HBV and HCVthe other factors such as aflatoxin, alcohol, obesity,diabetes and non-alcoholic fatty liver disease (NAFLD)might be responsible for a low prevalence of HCC inAsian countries. Currently available HCC therapies,chemotherapy, surgical are inefficient, mainly due tousually late diagnosis and high recurrence rates aftersurgical resection, and usually end with treatmentfailure. Liver transplantation also remains as a difficultstrategy in patients with HCC. Thus prevention of HCCby treating and prevention HBV and HCV infection,the major causative agents of HCC, and the other risk factors such as aflatoxin, alcohol, obesity

  14. Risk Analysis of Hepatocellular Carcinoma in Northeast China

    Institute of Scientific and Technical Information of China (English)

    Zhi-fang Jia; Meng Su; Miao He; Zhi-hua Yin; Wei Wu; Xue-lian Li; Peng Guan; Bao-sen Zhou

    2009-01-01

    Objective: It is known that chronic hepatitis B virus (HBV) infection is a main risk factor for hepatocellular carcinoma (HCC). To assess the effect of HBV infection and its interaction with other factors on the risk for HCC, a hospital-based case-control study was carried out in Northeast China. Methods: A total of 384 cases with hepatocellular carcinoma and 432 controls without evidence of liver diseases were enrolled in the study. Blood samples were collected to detect the serum markers of hepatitis B virus (HBV) and hepatitis C virus (HCV) and questionnaires about lifestyle and family tumor history were performed in all subjects. Results: The total infection rate of HBV in hepatocellular carcinoma cases was 70.8% and 10.0% in non-liver disease controls. There was a statistically significant difference (P<0.0001) between cases and controls (OR= 22.0; 95%CI:15.0-32.3). Interaction analysis indicated that in HBV chronic carriers with HCV infection or alcohol consumption or family HCC history, the risk for HCC increased (OR=41.1, 95%CI: 20.2-83.9, OR=125.0, 95%CI: 66.5-235.2; OR=56.9, 95%CI: 27.2-119.3 respectively). In addition, hepatitis B history, HCV infection, hepatic cirrhosis and family history of HCC were also potential HCC independent risk factors. Conclusion: We confirmed that HBV is a chief risk factor for hepatocellular carcinoma and accounts for 67.7% of all hepatocellular carcinoma in Northeast China. HCV infection, alcohol intake and family history could enhance the risk for HCC in chronic HBV carriers.

  15. Increased nociceptin/orphanin FQ plasma levels in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Ferenc Szalay; Mónika B Hantos; Andrea Horvath; Peter L. Lakatos; Aniko Folhoffer; Kinga Dunkel; Dalma Hegedus; Kornélia Tekes

    2004-01-01

    AIM: The heptadecapeptide nociceptin alias orphanin FQ is the endogenous agonist of opioid receptor-like1 receptor.It is involved in modulation of pain and cognition. High blood level was reported in patients with acute and chronic pain,and in Wilson disease. An accidental observation led us to investigate nociceptin in hepatocellular carcinoma.METHODS: Plasma nociceptin level was measured by radioimmunoassay, aprotinin was used as protease inhibitor.Hepatocellular carcinoma was diagnosed by laboratory,ultrasound, other imaging, and confirmed by fine needle biopsy. Results were compared to healthy controls and patients with other chronic liver diseases.RESULTS: Although nociceptin levels were elevated in patients with Wilson disease (14.0±2.7 pg/mL, n=26),primary biliary cirrhosis (12.1±3.2 pg/mL, n=21) and liver cirrhosis (12.8±4.0 pg/mL, n=15) compared to the healthy controls (9.2±1.8 pg/mL, n=29, P<0.001 for each), in patients with hepatocellular carcinoma a ten-fold increase was found (105.9±14.4 pg/mL, n=29, P<0.0001). High plasma levels were found in each hepatocellular carcinoma patient including those with normal alpha fetoprotein and those with pain (104.9±14.9 pg/mL, n=12) and without (107.7±14.5pg/mL, n=6).CONCLUSION: A very high nociceptin plasma level seems to be an indicator for hepatocellular carcinoma. Further research is needed to clarify the mechanism and clinical significance of this novel finding.

  16. Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Miura Seiki

    2012-02-01

    Full Text Available Abstract Background Although fibroblast growth factor 19 (FGF19 can promote liver carcinogenesis in mice, its involvement in human hepatocellular carcinoma (HCC has not been well investigated. FGF19, a member of the FGF family, has unique specificity for its receptor FGFR4. This study aimed to clarify the involvement of FGF19 in the development of HCC. Methods We investigated human FGF19 and FGFR4 expression in 40 hepatocellular carcinoma specimens using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR analysis and immunohistochemistry. Moreover, we examined the expression and the distribution of FGF19 and FGFR4 in 5 hepatocellular carcinoma cell lines (HepG2, HuH7, HLE, HLF, and JHH7 using RT-PCR and immunohistochemistry. To test the role of the FGF19/FGFR4 system in tumor progression, we used recombinant FGF19 protein and small interfering RNA (siRNA of FGF19 and FGFR4 to regulate their concentrations. Results We found that FGF19 was significantly overexpressed in HCCs as compared with corresponding noncancerous liver tissue (P FGF19 mRNA expression was an independent prognostic factor for overall and disease-free survival. Moreover, we found that the FGF19 recombinant protein could increase the proliferation (P n = 12 and invasion (P n = 6 capabilities of human hepatocellular carcinoma cell lines and inhibited their apoptosis (P n = 12. Inversely, decreasing FGF19 and FGFR4 expression by siRNA significantly inhibited proliferation and increased apoptosis in JHH7 cells (P n = 12. The postoperative serum FGF19 levels in HCC patients was significantly lower than the preoperative levels (P n = 29. Conclusions FGF19 is critically involved in the development of HCCs. Targeting FGF19 inhibition is an attractive potential therapeutic strategy for HCC.

  17. Hepatocellular carcinoma (Letter to the editor)

    DEFF Research Database (Denmark)

    Békássy, Albert N.; Garwicz, Stanislaw; Jensen, O.A.

    1994-01-01

    Øjenpatologi, Alagill's syndrome, hepatic carcinoma, biliary atresia, histopathology, liver, child, liver cirrhosis, autopsy, eyes, AFP......Øjenpatologi, Alagill's syndrome, hepatic carcinoma, biliary atresia, histopathology, liver, child, liver cirrhosis, autopsy, eyes, AFP...

  18. CHST13抑制肝癌细胞侵袭能力的研究%CHST13 inhibits the invasive property of human hepatocellular carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    李艳平; 刘有训; 马红叶; 王宁; 张旭

    2014-01-01

    Objective To clarify the association between chondroitin-4-O-sulfotransferase-3 (CHST13) and hepatoma metastasis by the research of differential expression of CHST13 in MHCC97-H and MHCC97-L human hepatocarcinoma cell lines,which have high and low metastatic potential,respectively,and to confirm novel target of hepatoma metastasis and anti-tumor therapy.Methods The differential expressions of CHST13 in MHCC97-H and MHCC97-L human hepatocarcinoma cell lines were analyzed by real-time PCR,Western blot.CHST13 was silenced using RNA interference approach to detect the invasive ability in vitro and tumorigenicity in vivo in MHCC97-L cells.Results The expression of CHST13 was different in MHCC97-L cells,as compared to those in MHCC97-H cells.Knockdown of CHST13 expression enhanced MHCC97-L cells invasion and tumorigenicity both in vitro (t =2.8,P =0.005) and in vivo (t =2.5,P =0.01).The quantity of cells which crossed basement membrane increased [(30 ± 3):(14 ± 2)],and the average weight of tumor increased [(0.9 ± 0.10) g:(0.5 ± 0.06) g].Conclusion The differential expressions of CHST13 in human hepatocarcinoma cell lines correlate with tumor invasion and tumorigenicity,and it is expected to be a novel target for the treatment of hepatocellular carcinoma.%目的 通过研究磺基转移酶CHST13在人肝癌高转移细胞株MHCC97-H和人肝癌低转移细胞株MHCC97-L中的差异表达,明确其与肝癌转移的相关性,从而证实肝癌转移诊断及抗肿瘤治疗新靶点.方法 采用实时PCR、Western blot分析磺基转移酶CHST13在人肝癌高、低转移细胞株的差异表达,通过RNA干扰技术干预CHST13基因,检测干扰前后MHCC97-L细胞的体外侵袭力及体内成瘤性.结果 CHST13在人肝癌高、低转移细胞株中表达具有明显差异;下调MHCC97-L细胞中CHST13基因表达后,穿过基底膜的细胞数量[(30±3)个]明显多于未处理组[(14±2)个],体外侵袭力显著增强(t=2.8,P=0.005);相对于正常细胞[(0

  19. Renal adenocarcinoma, hepatocellular carcinoma, and pancreatic islet cell carcinoma in a binturong (Arctictis binturong).

    Science.gov (United States)

    Klaphake, Eric; Shoieb, Ahmed; Ramsay, Ed; Schumacher, Juergen; Craig, Linden

    2005-03-01

    A 19-yr-old binturong (Arctictis binturong) with acute upper respiratory disease was euthanized. Postmortem findings included hepatocellular carcinoma, pancreatic islet cell carcinoma, and renal adenocarcinoma with metastasis to the spleen, pleura, and pericardium. A link between primary hepatic and renal neoplasms has been noted in older humans.

  20. Inhibition of Aurora A Kinase by Alisertib Induces Autophagy and Cell Cycle Arrest and Increases Chemosensitivity in Human Hepatocellular Carcinoma HepG2 Cells.

    Science.gov (United States)

    Zhu, Qiaohua; Yu, Xinfa; Zhou, Zhi-Wei; Zhou, Chengyu; Chen, Xiao-Wu; Zhou, Shu-Feng

    2017-01-01

    Aurora A kinase represent a feasible target in cancer therapy. To evaluate the proteomic response of human liver carcinoma cells to alisertib (ALS) and identify the molecular targets of ALS, we examined the effects of ALS on the proliferation, cell cycle, autophagy, apoptosis, and chemosensitivity in HepG2 cells. The stable-isotope labeling by amino acids in cell culture (SILAC) based quantitative proteomic study was performed to evaluate the proteomic response to ALS. Cell cycle distribution and apoptosis were assessed using flow cytometry and autophagy was determined using flow cytometry and confocal microscopy. Our SILAC proteomic study showed that ALS regulated the expression of 914 proteins, with 407 molecules being up-regulated and 507 molecules being down-regulated in HepG2 cells. Ingenuity pathway analysis (IPA) and KEGG pathway analysis identified 146 and 32 signaling pathways were regulated by ALS, respectively, which were associated with cell survival, programmed cell death, and nutrition-energy metabolism. Subsequently, the verification experiments showed that ALS remarkably arrested HepG2 cells in G2/M phase and led to an accumulation of aneuploidy via regulating the expression of key cell cycle regulators. ALS induced a marked autophagy in a concentration- and time-dependent manner via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Autophagy inhibition promoted the pro-apoptotic effect of ALS, indicating a cyto-protective role of ALS-induced autophagy. ALS increased the chemosensitivity of HepG2 cells to cisplatin and doxorubicin. Taken together, ALS induces autophagy and cell cycle arrest in HepG2 cells via PI3K/Akt/mTOR-mediated pathway. Autophagy inhibition may promote the anticancer effect of ALS and sensitize the chemotherapy in HepG2 cells. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Hepatocellular carcinoma arising from hepatocellular adenoma in a hepatitis B virus-associated cirrhotic liver

    Energy Technology Data Exchange (ETDEWEB)

    Seo, J.M. [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Lee, S.J., E-mail: lucia@skku.edu [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Kim, S.H. [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Park, C.K.; Ha, S.Y. [Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2012-04-15

    Hepatocellular adenoma (HCA) is a rare, benign proliferation of hepatocytes that occurs mostly in a normal liver and in extreme rare cases, occurs in a cirrhotic liver. Hepatocellular carcinomas (HCC) arising within HCA through malignant transformation is rare. The specific incidence and mechanism of malignant transformation has not been established, but the long term use of oral contraceptives is considered a causative agent. We report a case of HCC arising from HCA detected in a hepatitis B-related cirrhotic liver with serial radiologic images.

  2. Identification of 1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranoside as a Glycine N-Methyltransferase Enhancer by High-Throughput Screening of Natural Products Inhibits Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Rajni Kant

    2016-05-01

    Full Text Available Glycine N-methyltransferase (GNMT expression is vastly downregulated in hepatocellular carcinomas (HCC. High rates of GNMT knockout mice developed HCC, while overexpression of GNMT prevented aflatoxin-induced carcinogenicity and inhibited liver cancer cell proliferation. Therefore, in this study, we aimed for the identification of a GNMT inducer for HCC therapy. We established a GNMT promoter-driven luciferase reporter assay as a drug screening platform. Screening of 324 pure compounds and 480 crude extracts from Chinese medicinal herbs resulted in the identification of Paeonia lactiflora Pall (PL extract and the active component 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranoside (PGG as a GNMT inducer. Purified PL extract and PGG induced GNMT mRNA and protein expression in Huh7 human hepatoma cells and in xenograft tumors. PGG and PL extract had potent anti-HCC effects both in vitro and in vivo. Furthermore, PGG treatment induced apoptosis in Huh7 cells. Moreover, PGG treatment sensitized Huh7 cells to sorafenib treatment. Therefore, these results indicated that identifying a GNMT enhancer using the GNMT promoter-based assay might be a useful approach to find drugs for HCC. These data also suggested that PGG has therapeutic potential for the treatment of HCC.

  3. Sesamin induces cell cycle arrest and apoptosis through the inhibition of signal transducer and activator of transcription 3 signalling in human hepatocellular carcinoma cell line HepG2.

    Science.gov (United States)

    Deng, Pengyi; Wang, Chen; Chen, Liulin; Wang, Cheng; Du, Yuhan; Yan, Xu; Chen, Mingjie; Yang, Guangxiao; He, Guangyuan

    2013-01-01

    Sesamin, one of the most abundant lignans in sesame seeds, has been shown to exhibit various pharmacological effects. The aim of this study was to elucidate whether sesamin promotes cell cycle arrest and induces apoptosis in HepG2 cells and further to explore the underlying molecular mechanisms. Here, we found that sesamin inhibited HepG2 cell growth by inducing G2/M phase arrest and apoptosis. Furthermore, sesamin suppressed the constitutive and interleukin (IL)-6-induced signal transducer and activator of transcription 3 (STAT3) signalling pathway in HepG2 cells, leading to regulate the downstream genes, including p53, p21, cyclin proteins and the Bcl-2 protein family. Our studies showed that STAT3 signalling played a key role in sesamin-induced G2/M phase arrest and apoptosis in HepG2 cells. These findings provided a molecular basis for understanding of the effects of sesamin in hepatocellular carcinoma tumour cell proliferation. Therefore, sesamin may thus be a potential chemotherapy drug for liver cancer.

  4. Identification of 1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranoside as a Glycine N-Methyltransferase Enhancer by High-Throughput Screening of Natural Products Inhibits Hepatocellular Carcinoma.

    Science.gov (United States)

    Kant, Rajni; Yen, Chia-Hung; Lu, Chung-Kuang; Lin, Ying-Chi; Li, Jih-Heng; Chen, Yi-Ming Arthur

    2016-05-04

    Glycine N-methyltransferase (GNMT) expression is vastly downregulated in hepatocellular carcinomas (HCC). High rates of GNMT knockout mice developed HCC, while overexpression of GNMT prevented aflatoxin-induced carcinogenicity and inhibited liver cancer cell proliferation. Therefore, in this study, we aimed for the identification of a GNMT inducer for HCC therapy. We established a GNMT promoter-driven luciferase reporter assay as a drug screening platform. Screening of 324 pure compounds and 480 crude extracts from Chinese medicinal herbs resulted in the identification of Paeonia lactiflora Pall (PL) extract and the active component 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranoside (PGG) as a GNMT inducer. Purified PL extract and PGG induced GNMT mRNA and protein expression in Huh7 human hepatoma cells and in xenograft tumors. PGG and PL extract had potent anti-HCC effects both in vitro and in vivo. Furthermore, PGG treatment induced apoptosis in Huh7 cells. Moreover, PGG treatment sensitized Huh7 cells to sorafenib treatment. Therefore, these results indicated that identifying a GNMT enhancer using the GNMT promoter-based assay might be a useful approach to find drugs for HCC. These data also suggested that PGG has therapeutic potential for the treatment of HCC.

  5. Development of a gene therapy strategy to target hepatocellular carcinoma based inhibition of protein phosphatase 2A using the α-fetoprotein promoter enhancer and pgk promoter: an in vitro and in vivo study

    Directory of Open Access Journals (Sweden)

    Li Wei

    2012-11-01

    Full Text Available Abstract Background Hepatocellular carcinoma (HCC is one of the leading causes of cancer-related deaths worldwide. Current therapies are insufficient, making HCC an intractable disease. Our previous studies confirmed that inhibition of protein phosphatase 2A (PP2A may provide a promising therapeutic strategy for cancer. Unfortunately, constitutive expression of PP2A in normal tissues limits the application of PP2A inhibition. Thus, a HCC-specific gene delivery system should be developed. The α-fetoprotein (AFP promoter is commonly used in HCC-specific gene therapy strategies; however, the utility of this approach is limited due to the weak activity of the AFP promoter. It has been shown that linking the AFP enhancer with the promoter of the non-tissue-specific, human housekeeping phosphoglycerate kinase (pgk gene can generate a strong and HCC-selective promoter. Methods We constructed a HCC-specific gene therapy system to target PP2A using the AFP enhancer/pgk promoter, and evaluated the efficiency and specificity of this system both in vitro and in vivo. Results AFP enhancer/pgk promoter-driven expression of the dominant negative form of the PP2A catalytic subunit α (DN-PP2Acα exerted cytotoxic effects against an AFP-positive human hepatoma cell lines (HepG2 and Hep3B, but did not affect AFP-negative human hepatoma cells (SK-HEP-1 or normal human liver cells (L-02. Moreover, AFP enhancer/pgk promoter driven expression of DN-PP2Acα inhibited the growth of AFP-positive HepG2 tumors in nude mice bearing solid tumor xenografts, but did not affect AFP-negative SK-HEP-1 tumors. Conclusions The novel approach of AFP enhancer/pgk promoter-driven expression of DN-PP2Acα may provide a useful cancer gene therapy strategy to selectively target HCC.

  6. Growth arrest and apoptosis of human hepatocellular carcinoma cells induced by hexamethylene bisacetamide

    Science.gov (United States)

    Ouyang, Gao-Liang; Cai, Qiu-Feng; Liu, Min; Chen, Rui-Chuan; Huang, Zhi; Jiang, Rui-Sheng; Chen, Fu; Hong, Shui-Gen; Bao, Shi-Deng

    2004-01-01

    AIM: To investigate the cellular effects of hybrid polar compound hexamethylene bisacetamide (HMBA) on the growth and apoptosis of human hepatocellular carcinoma cells and to provide the molecular mechanism for potential application of HMBA in the treatment of liver cancer. METHODS: Effects of HMBA on the growth of human hepatocellular carcinoma SMMC-7721 cells were assayed by MTT chronometry. Apoptosis induced by HMBA was detected by phase-contrast microscopy, flow cytometry, propidium iodide staining and immunocytochemical analysis. RESULTS: The growth of SMMC-7721 cells was significantly inhibited by HMBA, and the growth inhibitory rate was 51.1%, 62.6%, 68.7% and 73.9% respectively after treatment with 5.0, 7.5, 10.0 and 12.5 mmol/L of HMBA. In the cells treated with 10 mmol/L of HMBA for 72 h, the population of cells at sub-G1 phase significantly increased, and the apoptotic bodies and condensed nuclei were detected. Moreover, treatment of SMMC-7721 cells with 10 mmol/L of HMBA down-regulated the expression of Bcl-2 anti-apoptotic protein, while slightly up-regulated the level of pro-apoptotic protein Bax. CONCLUSION: Treatment with 10.0 mmol/L of HMBA can significantly inhibit the growth and induce apoptosis of human hepatocellular carcinoma SMMC-7721 cells by decreasing the ratio of Bcl-2 to Bax. PMID:15052673

  7. Growth arrest and apoptosis of human hepatocellular carcinoma cells induced by hexamethylene bisacetamide

    Institute of Scientific and Technical Information of China (English)

    Gao-Liang Ouyang; Qiu-Feng Cai; Min Liu; Rui-Chuan Chen; Zhi Huang; Rui-Sheng Jiang; Fu Chen; Shui-Gen Hong; Shi-Deng Bao

    2004-01-01

    AIM: To investigate the cellular effects of hybrid polar compound hexamethylene bisacetamide (HMBA) on the growth and apoptosis of human hepatocellular carcinoma cells and to provide the molecular mechanism for potential application of HMBA in the treatment of liver cancer.METHODS: Effects of HMBA on the growth of human hepatocellular carcinoma SMMC-7721 cells were assayed by MTT chronometry. Apoptosis induced by HMBA was detected by phase-contrast microscopy, flow cytometry,propidium iodide staining and immunocytochemical analysis.RESULTS: The growth of SMMC-7721 cells was significantly inhibited by HMBA, and the growth inhibitory rate was 51.1%, 62.6%, 68.7% and 73.9% respectively after treatment with 5.0, 7.5, 10.0 and 12.5 mmol/L of HMBA.In the cells treated with 10 mmol/L of HMBA for 72 h, the population of cells at sub-G1 phase significantly increased,and the apoptotic bodies and condensed nuclei were detected. Moreover, treatment of SMMC-7721 cells with 10 mmol/L of HMBA down-regulated the expression of Bcl2 anti-apoptotic protein, while slightly up-regulated the level of pro-apoptotic protein Bax.CONCLUSION: Treatment with 10.0 mmol/L of HMBA can significantly inhibit the growth and induce apoptosis of human hepatocellular carcinoma SMMC-7721 cells by decreasing the ratio of Bcl-2 to Bax.

  8. Cationic poly(amidoamine) dendrimers induced cyto-protective autophagy in hepatocellular carcinoma cells

    Science.gov (United States)

    Li, Yubin; Wang, Shaofei; Wang, Ziyu; Qian, Xiaolu; Fan, Jiajun; Zeng, Xian; Sun, Yun; Song, Ping; Feng, Meiqing; Ju, Dianwen

    2014-09-01

    Poly(amidoamine) (PAMAM) dendrimers are proposed as one of the most promising nanomaterials for biomedical applications because of their unique tree-like structure, monodispersity and tunable properties. In this study, we found that PAMAM dendrimers could induce the formation of autophagosomes and the conversion of microtubule-associated protein 1 light chain 3 (LC3) in hepatocellular carcinoma HepG2 cells, while the inhibition of the Akt/mTOR and activation of the Erk 1/2 signaling pathways were involved in autophagy-induced by PAMAM dendrimers. We also investigated the suppression of autophagy with the obviously enhanced cytotoxicity of PAMAM dendrimers. Moreover, the blockage of a reactive oxygen species (ROS) could enhance the growth inhibition and apoptosis of hepatocellular carcinoma cells, induced by PAMAM dendrimers through reducing autophagic effects. Taken together, these findings explored the role and mechanism of autophagy induced by PAMAM dendrimers in HepG2 cells, provided new insight into the effect of autophagy on drug delivery nanomaterials and tumor cells and contributed to the use of a drug delivery vehicle for hepatocellular carcinoma treatment.

  9. Targeting FGF19/FGFR4 Pathway: A Novel Therapeutic Strategy for Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Dimitra Repana

    2015-10-01

    Full Text Available Hepatocellular carcinoma (HCC is a lethal cancer with limited systemic therapeutic options. Liver carcinogenesis is a complex procedure and various pathways have been found to be deregulated which are potential targets for novel treatments. Aberrant signalling through FGF19 and its receptor FGFR4 seems to be the oncogenic driver for a subset of HCCs and is associated with poor prognosis. Inhibition of the pathway in preclinical models has shown antitumour activity and has triggered further evaluation of this strategy to in vivo models. This review aims to describe the role of the FGF19/FGFR4 pathway in hepatocellular carcinoma and its role as a potential predictive biomarker for novel targeted agents against FGF19/FGFR4 signalling.

  10. Clinical and laboratory features of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Andrés Cárdenas

    2007-02-01

    Full Text Available

    The clinical presentation of hepatocellular carcinoma (HCC differs between patients in developing countries (African and Chinese populations from those in industrialized countries. In industrialized countries, HCC co-exists with symptomatic cirrhosis in 80% of cases and clinical manifestations are usually related to those of the underlying disease. On the other hand, patients from developing countries have HCC and cirrhosis in approximately 40% of cases. Underlying cirrhosis in many cases is not advanced and does not produce any symptoms or associated symptoms are masked by those of the tumor (right upper quadrant pain, mass in the upper abdomen, weight loss and weakness. In a subset of patients, there are no clinical manifestations as HCC may occur in the context of hepatitis B infection without cirrhosis.

    Clinical Manifestations

    In Western countries, nearly 35% percent of patients with HCC are asymptomatic. Some of the most common clinical manifestations include: abdominal pain (53-58% of patients, especially in epigastrium or right upper quadrant, abdominal mass (30%, weight loss, malaise, anorexia, cachexia, jaundice or fever.

    Physical Exam

    Physical findings vary with the stage of disease. The patient may exhibit slight or moderate wasting when first seen. In patients with cirrhosis, typical stigmata of chronic liver disease may be present. In advanced stages of HCC the liver may be enlarged and there is significant tenderness. An arterial bruit may be heard over the liver

  11. MicroRNA-429 Modulates Hepatocellular Carcinoma Prognosis and Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Xiao-Ying Huang

    2013-01-01

    Full Text Available MicroRNA-429 (miR-429 may modify the development and progression of cancers; however, the role of this microRNA in the hepatocellular carcinoma (HCC has not been well elaborated. Here, we tested miR-429 expression in 138 pathology-diagnosed HCC cases and SMMC-7721 cells. We found that miR-429 was upregulated in HCC tumor tissues and that the high expression of miR-429 was significantly correlated with larger tumor size (odd ratio (OR, 2.70; 95% confidence interval (CI, 1.28–5.56 and higher aflatoxin B1-DNA adducts (OR = 3.13, 95% CI = 1.47–6.67. Furthermore, this microRNA overexpression modified the recurrence-free survival and overall survival of HCC patients. Functionally, miR-429 overexpression progressed tumor cells proliferation and inhibited cell apoptosis. These results indicate for the first time that miR-429 may modify HCC prognosis and tumorigenesis and may be a potential tumor therapeutic target.

  12. Asialoglycoprotein receptor targeted delivery of doxorubicin nanoparticles for hepatocellular carcinoma.

    Science.gov (United States)

    Pranatharthiharan, Sandhya; Patel, Mitesh D; Malshe, Vinod C; Pujari, Vaishali; Gorakshakar, Ajit; Madkaikar, Manisha; Ghosh, Kanjaksha; Devarajan, Padma V

    2017-11-01

    We report asialoglycoprotein receptor (ASGPR)-targeted doxorubicin hydrochloride (Dox) nanoparticles (NPs) for hepatocellular carcinoma (HCC). Polyethylene sebacate (PES)-Gantrez® AN 119 Dox NPs of average size 220 nm with PDI < 0.62 and ∼20% Dox loading were prepared by modified nanoprecipitation. ASGPR ligands, pullulan (Pul), arabinogalactan (AGn), and the combination (Pul-AGn), were anchored by adsorption. Ligand anchoring enabled high liver uptake with a remarkable hepatocyte:nonparenchymal cell ratio of 85:15. Furthermore, Pul-AGn NPs exhibited an additive effect implying incredibly high hepatocyte accumulation. Galactose-mediated competitive inhibition confirmed ASGPR-mediated uptake of ligand-anchored NPs in HepG2 cell lines. Subacute toxicity in rats confirmed the safety of the NP groups. However, histopathological evaluation suggested mild renal toxicity of AGn. Pul NPs revealed sustained reduction in tumor volume in PLC/PRF/5 liver tumor-bearing Nod/Scid mice up to 46 days. Extensive tumor necrosis, reduced collagen content, reduction in the HCC biomarker serum α-fetoprotein (p < 0.05), a mitotic index of 1.135 (day 46), and tumor treated/tumor control (T/C) values of <0.42 signified superior efficacy of Pul NPs. Furthermore, weight gain in the NP groups, and no histopathological alterations indicated that they were well tolerated by the mice. The high efficacy coupled with greater safety portrayed Pul Dox NPs as a promising nanocarrier for improved therapy of HCC.

  13. Chemopreventive Potential of Green Tea Catechins in Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Masahito Shimizu

    2015-03-01

    Full Text Available Hepatocellular carcinoma (HCC, which is a common malignancy worldwide, usually develops in a cirrhotic liver due to hepatitis virus infection. Metabolic syndrome, which is frequently complicated by obesity and diabetes mellitus, is also a critical risk factor for liver carcinogenesis. Green tea catechins (GTCs may possess potent anticancer and chemopreventive properties for a number of different malignancies, including liver cancer. Antioxidant and anti-inflammatory activities are key mechanisms through which GTCs prevent the development of neoplasms, and they also exert cancer chemopreventive effects by modulating several signaling transduction and metabolic pathways. Furthermore, GTCs are considered to be useful for the prevention of obesity- and metabolic syndrome-related carcinogenesis by improving metabolic disorders. Several interventional trials in humans have shown that GTCs may ameliorate metabolic abnormalities and prevent the development of precancerous lesions. The purpose of this article is to review the key mechanisms by which GTCs exert chemopreventive effects in liver carcinogenesis, focusing especially on their ability to inhibit receptor tyrosine kinases and improve metabolic abnormalities. We also review the evidence for GTCs acting to prevent metabolic syndrome-associated liver carcinogenesis.

  14. 18β-甘草次酸抑制肝癌细胞生长的实验研究%Experimental study of18-glycyrrhetinic acid inhibiting growth of hepatocellular carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    周长升; 芶欣; 王效民; 黄建钊

    2016-01-01

    Objective: To investigate the effect of 18β-glycyrrhetinic acid (GA) on growth of hepatocellular carcinoma cells. Methods: hTe hepatocellular carcinoma cells (Hepa1-6) and normal hepatic cells (AML-12) were exposed to different concentrations of GA or adriamycin (ADM) for different time periods, atfer that, the cell growth inhibition and half inhibitory concentration (IC50) were analyzed. hTen, atfer Hepa1-6 cells were treated with GA of an appropriate concentration selected according to IC50 for a certain time period, the cell apoptosis was measured. Results: Low concentrations of GA exerted no obvious inhibitory effects on proliferations of the two types of cells, but had remarkable inhibitory effects on proliferations of them at the concentrations >8 µg/mL, and the effects were increased with the elevation of the GA concentration and time prolongation. All concentrations of ADM showed evident inhibitory effects on proliferations of the two types of cells, and these effects were increased with the rising of the ADM concentration but decreased as time elapsed. hTe IC50 of GA for Hepa1-6 cells was lower than that for AML-12 cells, and the IC50 difference between them reached a largest value at 48 h treatment, while the IC50 of ADM for Hepa1-6 cells was higher than that for AML-12 cells at any time period of treatment. Atfer treatment with 25 µg/mL GA for 48 h (under this condition, the inhibition rate of proliferation in Hepa1-6 cells was 50%, while in AML-12 cells was only 3.8%), the apoptosis in Hepa1-6 cells was signiifcantly increased, which mainly resulted from early apoptosis (P Conclusion: GA can inhibit the growth of hepatocellular carcinoma cells and the mechanism may be related to its inducing cells apoptosis. GA may be safer and has less toxic side effects for treatment of hepatocellular carcinoma.%目的:探讨18β-甘草次酸(GA)对肝癌细胞生长的影响。  方法:用不同浓度的GA或阿霉素

  15. SIRT1 and c-Myc Promote Liver Tumor Cell Survival and Predict Poor Survival of Human Hepatocellular Carcinomas

    Science.gov (United States)

    Jang, Kyu Yun; Noh, Sang Jae; Lehwald, Nadja; Tao, Guo-Zhong; Bellovin, David I.; Park, Ho Sung; Moon, Woo Sung; Felsher, Dean W.; Sylvester, Karl G.

    2012-01-01

    The increased expression of SIRT1 has recently been identified in numerous human tumors and a possible correlation with c-Myc oncogene has been proposed. However, it remains unclear whether SIRT1 functions as an oncogene or tumor suppressor. We sought to elucidate the role of SIRT1 in liver cancer under the influence of c-Myc and to determine the prognostic significance of SIRT1 and c-Myc expression in human hepatocellular carcinoma. The effect of either over-expression or knock down of SIRT1 on cell proliferation and survival was evaluated in both mouse and human liver cancer cells. Nicotinamide, an inhibitor of SIRT1, was also evaluated for its effects on liver tumorigenesis. The prognostic significance of the immunohistochemical detection of SIRT1 and c-Myc was evaluated in 154 hepatocellular carcinoma patients. SIRT1 and c-Myc regulate each other via a positive feedback loop and act synergistically to promote hepatocellular proliferation in both mice and human liver tumor cells. Tumor growth was significantly inhibited by nicotinamide in vivo and in vitro. In human hepatocellular carcinoma, SIRT1 expression positively correlated with c-Myc, Ki67 and p53 expression, as well as high á-fetoprotein level. Moreover, the expression of SIRT1, c-Myc and p53 were independent prognostic indicators of hepatocellular carcinoma. In conclusion, this study demonstrates that SIRT1 expression supports liver tumorigenesis and is closely correlated with oncogenic c-MYC expression. In addition, both SIRT1 and c-Myc may be useful prognostic indicators of hepatocellular carcinoma and SIRT1 targeted therapy may be beneficial in the treatment of hepatocellular carcinoma. PMID:23024800

  16. The Effect of Nano-apatite on the Expression of Telomerase Gene of Human Hepatocellular Carcinoma Cells

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    To investigate the effect of nano- apatite on the expression of the telomerase gene of human hepatocellular carcinoma cell lines and further explore the mechanism of the nano-apatite inhibiting cancer cells. Using the hybridization in situ method to detect the expression of the telomerase gene of human hepatocellular carcinoma cells treated with the nano- apatite for 4 h at 37 ℃. The hybridization in situ showed that the cytoplasm of the positive cells was stained in nigger-brown. The positive cell rate of the control group was 88.49% , the cisplatin group was 25.6% , the nano-apatite group was 63.6% . The activity oftelomerase gene was both obviously declined comparing with the control group and the difference had significance (p < 0.05, p < 0.01 ). The nanoapatite obviously inhabit the expression of the telomerase gene of human hepatocellular carcinoma cells.

  17. Emerging role of dual antiplatelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Aiolfi R

    2014-11-01

    Full Text Available Roberto Aiolfi, Giovanni Sitia Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy Abstract: Platelets, the chief effectors of vascular homeostasis, have been identified as important players in the pathogenesis of both acute and chronic liver disease in preclinical models of hepatitis B viral infection. Platelets are thought to promote the accumulation of virus-specific T-cells into the liver parenchyma. Importantly, the inhibition of platelet activation by clinically relevant doses of aspirin and clopidogrel was able to reduce immune-mediated necroinflammatory liver disease, extracellular matrix deposition, and hepatocellular carcinoma development; the same treatment was able to improve overall survival. These results strongly support the design of clinical trials aiming to define the potential of antiplatelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma. Keywords: platelets, hepatocellular carcinoma, hepatitis B virus

  18. Hepatocellular carcinoma in urban born blacks: frequency and relation to hepatitis B virus infection.

    OpenAIRE

    Kew, M. C.; Kassianides, C; Hodkinson, J; Coppin, A; Paterson, A. C.

    1986-01-01

    Chronic hepatitis B virus infection is far less common in urban born than in rural born southern African blacks, who also have a high incidence of hepatocellular carcinoma. A case-control study was carried out to determine the relative frequency of hepatocellular carcinoma and its relation to hepatitis B virus infection in urban born blacks. Three hundred and ninety two black patients with hepatocellular carcinoma and matched controls seen at two city hospitals were classified by questioning ...

  19. Sann-Joong-Kuey-Jian-Tang inhibits hepatocellular carcinoma Hep-G2 cell proliferation by increasing TNF-α, Caspase-8, Caspase- 3 and Bax but by decreasing TCTP and Mcl-1 expression in vitro.

    Science.gov (United States)

    Chen, Yao-Li; Yan, Meng-Yi; Chien, Su-Yu; Kuo, Shou-Jen; Chen, Dar-Ren; Cheng, Chun-Yuan; Su, Chin-Cheng

    2013-05-01

    Hepatic cancer remains a challenging disease and there is a need to identify new treatments. Sann-Joong-Kuey-Jian-Tang (SJKJT), a traditional medicinal prescription, has been used to treat lymphadenopathy and exhibits cytotoxic activity in many types of human cancer cells. Our previous studies revealed that SJKJT is capable of inhibiting colon cancer colo 205 cells by inducing autophagy and apoptosis. However, the effects and molecular mechanisms of SJKJT in human hepatocellular carcinoma have not been clearly elucidated. In the present study we evaluated the effects of SJKJT in human hepatic cellular carcinoma Hep-G2 cells. The cytotoxicity of SJKJT in Hep-G2 cells was measured by MTT assay. The cell cycles were analyzed by fluorescence‑activated cell sorting (FACS). The protein expression of translationally controlled tumor protein (TCTP), Mcl-1, Fas, TNF-α, Caspase-8, Caspase-3 and Bax in Hep-G2 cells treated with SJKJT was evaluated by western blotting. The protein expression of Caspase-3 was also detected by immunofluorescence staining. The results showed that SJKJT inhibits Hep-G2 cells in a time- and dose‑dependent manner. During SJKJT treatment for 48 and 72 h, the half-maximum inhibitory concentration (IC50) was 1.48 and 0.94 mg/ml, respectively. The FACS results revealed that increased doses of SJKJT were capable of increasing the percentage of cells in the sub-G1 phase. Immunofluorescence staining showed that Hep-G2 treated with SJKJT had increased expression of Caspase-3. The western blot results showed that the protein expression of Fas, TNF-α, Caspase-8, Caspase- 3 and Bax was upregulated, but that of TCTP and Mcl-1 was downregulated in Hep-G2 cells treated with SJKJT. In conclusion, these findings indicated that SJKJT inhibits Hep-G2 cells. One of the molecular mechanisms responsible for this may be the increased Fas, TNF-α, Caspase-8, Caspase- 3 and Bax expression; another mechanism may be via decreasing TCTP and Mcl-1 expression in order

  20. Non-surgical management of hepatocellular carcinoma; Prise en charge non chirurgicale du carcinome hepatocellulaire

    Energy Technology Data Exchange (ETDEWEB)

    Merle, P. [Service d' hepato-gastroenterologie, hopital de l' Hotel-Dieu, 69 - Lyon (France); Inserm U871 -Oncogenese hepatique et hepatites virales-, 69 - Lyon (France); IFR62 Lyon-Est, universite Lyon 1, 69 - Lyon (France); Mornex, F. [Departement de radiotherapie-oncologie, centre hospitalier Lyon-Sud, 69 - Pierre-Benite (France)

    2010-10-15

    Most of patients with hepatocellular carcinoma (HCC) cannot benefit from surgical therapies. Among non-surgical options, only radiofrequency can challenge surgery for small size tumours. Conformal radiotherapy is likely highly efficient on solitary tumours, but controlled studies are warranted to conclude. Other options are purely palliative. Trans-arterial hepatic chemo-embolization is the goal-standard for multifocal hepatocellular carcinoma and Sorafenib for hepatocellular carcinoma with portal vein invasion, leading to modest but significant benefit on survival rates. Yttrium-90 radio-embolization is under evaluation through controlled studies, and could be of major interest for multifocal hepatocellular carcinoma with or without portal venous invasion. (authors)

  1. Mechanisms and signiifcance of lipoprotein(a) in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Jing-Ting Jiang; Chang-Ping Wu; Ning Xu; Xue-Guang Zhang

    2009-01-01

    BACKGROUND: The liver plays a key role in the metabolism of plasma apolipoproteins, endogenous lipids and lipoproteins. Hepatocellular carcinoma is one of the most common fatal malignant tumors in China and in other Southeast Asian countries. It has been demonstrated that plasma lipid proifles are changed in liver cancer. DATA SOURCES: A MEDLINE database search was performed to identify relevant articles using the keywords "hepatocellular carcinoma" and "lipoprotein(a)". The search was conducted and research articles were reviewed from 1960 to 2008. RESULTS: Production and homeostasis of lipids, apo-lipoproteins and lipoproteins depend on the integrity of hepatocellular functions, which ensures normal lipid and lipoprotein metabolismin vivo. When hepatocellular injury or liver cancer occurs these processes can be impaired. It has been suggested that plasma levels of apolipoprotein(a) (apo(a)) and/or lipoprotein(a) (Lp(a)) may be considered as sensitive markers of hepatic impairment. CONCLUSIONS: Plasma levels of apo(a) and Lp(a) display signiifcant correlations with hepatic status. Most studies demonstrated that the plasma levels of apo(a) and Lp(a) can be considered as an additional clinical index of liver function.

  2. Cytogenetic and molecular genetic alterations in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Sze-hang LAU; Xin-yuan GUAN

    2005-01-01

    Specific chromosome aberrations are frequently detected during the development of hepatocellular carcinoma. Molecular cytogenetic approaches such as comparative genomic hybridization and loss of heterozygosity analyses have provided fruitful information on changes in HCC cases at the genomic level. Mapping of chromosome gains and losses have frequently resulted in the identification of oncogenes and tumor suppressors, respectively. In this review, we summarize some frequently detected chromosomal aberrations reported for hepatocellular carcinoma cases using comparative genomic hybridization and loss of heterozygosity studies. Focus will be on gains of 1q, 8q, and 20q, and losses of 4q,8p, 13q, 16q, and 17p. We then examine the candidate oncogenes and tumor suppressors located within these regions, and explore their possible functions in hepatocarcinogenesis. Finally, the impact of microarray-based screening platforms will be discussed.

  3. Magnetic Nanoparticles for Hepatocellular Carcinoma Diagnosis and Therapy

    DEFF Research Database (Denmark)

    Ungureanu, Bogdan Silviu; Teodorescu, Cristian-Mihail; Săftoiu, Adrian

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver, ranking as the second most common cause of death from cancer worldwide. Magnetic nanoparticles (MNPs) have been used so far in tumor diagnosis and treatment, demonstrating great potential and promising results. In princ......Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver, ranking as the second most common cause of death from cancer worldwide. Magnetic nanoparticles (MNPs) have been used so far in tumor diagnosis and treatment, demonstrating great potential and promising results...... and treatment of liver cancer and offers a walkthrough from the MNPs imaging applicability to further therapeutic options, including their potential flaws. The MNP unique physical and biochemical properties will be mentioned in close relationship to their subsequent effects on the human body, and, also......, their toxic potential will be noted. A presentation of what barriers the MNPs should overcome to be more successful will conclude this review....

  4. Hepatocellular carcinoma: Implications for Asia-Pacific Oncology Nurses

    Directory of Open Access Journals (Sweden)

    Deborah A Boyle

    2017-01-01

    Full Text Available Hepatocellular carcinoma (HCC is a prominent malignancy in the Asia-Pacific region. Despite considerable knowledge about it's scope and nature this malignancy remains incurable. This manuscript reviews the epidemiology of this cancer, its pathogenesis, risk factors, potential prevention, surveillance, treatment, and the oncology nurses' role relative to this malignancy. A literature search from the past decade was performed using the PubMed and CINAHL databases using the search terms “hepatocellular carcinoma,” “Asia,” and “nursing issues”. Themes such as etiology, prevention, treatment, and prognosis were included in this synthesis which has particular relevance to oncology nurses within the Asia-Pacific region.

  5. Surgical treatment of hepatocellular carcinoma with severe intratumoral arterioportal shunt

    Institute of Scientific and Technical Information of China (English)

    Hiromichi; Ishii; Teruhisa; Sonoyama; Shingo; Nakashima; Hiroyuki; Nagata; Atsushi; Shiozaki; Yoshiaki; Kuriu; Hisashi; Ikoma; Masayoshi; Nakanishi; Daisuke; Ichikawa; Hitoshi; Fujiwara; Kazuma; Okamoto; Toshiya; Ochiai; Yukihito; Kokuba; Chohei; Sakakura; Eigo; Otsuji

    2010-01-01

    We report a case of hepatocellular carcinoma (HCC) that caused a severe arterioportal shunt (APS). A 49-year-old man was admitted to hospital due to esophagogastric variceal hemorrhage and HCC, and underwent endoscopic variceal ligation (EVL) and endoscopic injection sclerotherapy (EIS). He was then referred to our hospital. Abdominal computed tomography revealed a lowdensity lesion in the posterior segment of the liver and an intratumoral APS, which caused portal hypertension. Although the patient underwen...

  6. Hepatic artery pseudoaneurysms arising from within a hepatocellular carcinoma

    Science.gov (United States)

    Chingkoe, C M; Chang, S D; Legiehn, G M; Weiss, A

    2010-01-01

    We report a case of a 70-year-old man with a large hepatocellular carcinoma (HCC) containing two pseudoaneurysms measuring up to 2 cm in diameter. The pseudoaneurysms and part of the HCC were supplied by branches from the middle colic artery, which arises from the superior mesenteric artery. This complex arterial vasculature was visualised on CT and confirmed with conventional angiography. PMID:21088082

  7. Surgical spacer placement and proton radiotherapy for unresectable hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Shohei; Komatsu; Yuichi; Hori; Takumi; Fukumoto; Masao; Murakami; Yoshio; Hishikawa; Yonson; Ku

    2010-01-01

    Few potentially curative treatment options exist apart from hepatic resection for patients with huge hepatocellular carcinoma (HCC). Proton radiotherapy is a promising new modality which has an inherent antitumor effect against HCC. However, the application of proton radiotherapy for tumors adjacent to the gastrointestinal tract is restricted because the tolerance dose of the intestine is extremely low. A novel two-step treatment was developed with surgical spacer placement and subsequent proton radiotherap...

  8. A case report of hepatocellular carcinoma in common hepatic duct

    Energy Technology Data Exchange (ETDEWEB)

    Song, Chi Sung; Park, In Ae; Choi, Sang Woon; Chung, Jung Kee [YongDeungPo City Hospital, Seoul (Korea, Republic of)

    1989-08-15

    We experienced a rare case of intraductal (common hepatic duct) hepatocellular carcinoma. Review of the literature disclosed 30 cases or less in which common duct involvement was a predominant clinical feature. Well demarcated, ovoid filling defect mass in CHD without parenchymal tumor mass was noted in ultrasound, PTC and CT study. The liver was cirrhotic, but {alpha}-fetoprotein level was normal. Differential diagnosis especially with Klatskin tumor is important and thought to be possible.

  9. Right ventricular exclusion for hepatocellular carcinoma metastatic to the heart

    Directory of Open Access Journals (Sweden)

    Fan Shou-Zen

    2010-10-01

    Full Text Available Abstract We used for the first time a right ventricular exclusion procedure for the treatment of hepatocellular carcinoma metastatic to the right ventricle. Our case report shows that this surgical option can be effective as rescue therapy for right ventricular outflow tract obstruction secondary to myocardial metastasis in critically ill patients. Most notably, this technique can prevent inadvertent dislodgement of tumor cells.

  10. Hepatocellular carcinoma: Advances in diagnosis, management, and long term outcome

    OpenAIRE

    Bodzin, AS; Busuttil, RW

    2015-01-01

    © 2015 Baishideng Publishing Group Inc. Hepatocellular carcinoma (HCC) remains a common and lethal malignancy worldwide and arises in the setting of a host of diseases. The incidence continues to increase despite multiple vaccines and therapies for viruses such as the hepatitis B and C viruses. In addition, due to the growing incidence of obesity in Western society, there is anticipation that there will be a growing population with HCC due to non-alcoholic fatty liver disease. Due to the grow...

  11. Dose response relationship in local radiotherapy for hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Park, Hee Chul; Seong, Jin Sil; Han, Kwang Hyub; Chon, Chae Yoon; Moon, Young Myoung; Song, Jae Seok; Suh, Chang Ok [College of Medicine, Yonsei Univ., Seoul (Korea, Republic of)

    2001-06-01

    In this study, it was investigated whether dose response relation existed or not in local radiotherapy for primary hepatocellular carcinoma. From January 1992 to March 2000, 158 patients were included in present study. Exclusion criteria included the presence of extrahepatic metastasis, liver cirrhosis of Child's class C, tumors occupying more than two thirds of the entire liver, and performance status on the ECOG scale of more than 3. Radiotherapy was given to the field including tumor with generous margin using 6, 10-MV X-ray. Mean tumor dose was 48.2{+-}7.9 Gy in daily 1.8 Gy fractions. Tumor response was based on diagnostic radiologic examinations such as CT scan, MR imaging, hepatic artery angiography at 4-8 weeks following completion of treatment. Statistical analysis was done to investigate the existence of dose response relationship of local radiotherapy when it was applied to the treatment of primary hepatocellular carcinoma. An objective response was observed in 106 of 158 patients, giving a response rate of 67. 1%. Statistical analysis revealed that total dose was the most significant factor in relation to tumor response when local radiotherapy was applied to the treatment of primary hepatocellular carcinoma. Only 29.2% showed objective response in patients treated with dose less than 40 Gy, while 68.6% and 77.1 % showed major response in patients with 40-50 Gy and more than 50 Gy, respectively. Child-Pugh classification was significant factor in the development of ascites, overt radiation induced liver disease and gastroenteritis. Radiation dose was an important factor for development of radiation induced gastroduodenal ulcer. Present study showed the existence of dose response relationship in local radiotherapy for primary hepatocellular carcinoma. Only radiotherapy dose was a significant factor to predict the objective response. Further study is required to predict the maximal tolerance dose in consideration of liver function and non

  12. Hepatocellular carcinoma HBsAg positive in pregnancy.

    Science.gov (United States)

    Gonçalves, C S; Pereira, F E; de Vargas, P R; Ferreira, L S

    1984-01-01

    The authors present a case of hepatocellular carcinoma diagnosed in a pregnant woman (four months pregnancy). The clinical evolution was complicated because of a severe hypoglicemia and the patient died 12 weeks after admission. The fetus died before a tentative of surgical delivery. The patient was HBsAg positive and five out of eight sons (inclusively the fetus), were HBsAg positive. There was not indication that the pregnancy had enhanced the tumor evolution.

  13. Hepatocellular carcinoma and liver metastases: Diagnosis and treatment

    Energy Technology Data Exchange (ETDEWEB)

    Hoogewoud, H.M.

    1993-12-31

    The state of the art concerning hepatocellular carcinoma and liver metastases is given in this review of the literature. The results of the author`s analysis are frequently summarized in tables that are easy to understand. The book covers the broad range of possible diagnostic and management techniques: pathology, imaging, surgery, radiotherapy and chemotherapy. The gamut of indications, contra-indications, results and complications is discussed. Emphasis is placed particularly on catheter techniques. (orig.). 41 figs., 21 tabs.

  14. Decreased PCSK9 expression in human hepatocellular carcinoma

    OpenAIRE

    2015-01-01

    Background The management of hepatocellular carcinoma (HCC) is limited by the lack of adequate screening biomarkers and chemotherapy. In response, there has been much interest in tumor metabolism as a therapeutic target. PCSK9 stimulates internalization of the LDL-receptor, decreases cholesterol uptake into hepatocytes and affects liver regeneration. Thus, we investigated whether PCSK9 expression is altered in HCC, influencing its ability to harness cholesterol metabolism. Methods Thirty-nine...

  15. Heparanase and hepatocellular carcinoma:Promoter or inhibitor?

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Heparan sulphate proteoglycans (HSPGs) consist of a core protein and several heparan sulphate (HS) side chains covalently linked. HS also binds a great deal of growth factors, chemokines, cytokines and enzymes to the extracellular matrix and cell surface. Heparanase can specially cleave HS side chains from HSPGs. There are a lot of conflicting reports about the role of heparanase in hepatocellular carcinoma (HCC). Heparanase is involved in hepatitis B virus infection and hepatitis C virus infection, the act...

  16. Hepatocellular carcinoma occurring in a Crohn’s disease patient

    Institute of Scientific and Technical Information of China (English)

    Mitsuaki; Ishida; Shigeyuki; Naka; Hisanori; Shiomi; Tomoyuki; Tsujikawa; Akira; Andoh; Tamio; Nakahara; Yasuharu; Saito; Yoshi-hide; Fujiyama; Mikiko; Takikita-Suzuki; Fumiyoshi; Kojima; Machiko; Hotta; Tohru; Tani; Yoshimasa; Kurumi; Hidetoshi; Okabe

    2010-01-01

    We report a case of hepatocellular carcinoma (HCC) occurring in a patient with Crohn’s disease (CD) without chronic hepatitis or liver cirrhosis, and review the clinicopathological features of HCC in CD patients. A 37-year-old Japanese man with an 8-year history of CD and a medication history of azathioprine underwent resection of a liver tumor. The histopathology of the liver tumor was pseudoglandular type HCC. In the nonneoplastic liver, focal hepatocyte glycogenosis (FHG) was observed, however, there was...

  17. Thymostimulin in advanced hepatocellular carcinoma: A phase II trial

    Directory of Open Access Journals (Sweden)

    Behl Susanne

    2008-03-01

    Full Text Available Abstract Background Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma in vitro. In a phase II trial, we investigated safety and efficacy including selection criteria for best response in advanced or metastasised hepatocellular carcinoma. Methods 44 patients (84 % male, median age 69 years not suitable or refractory to conventional therapy received thymostimulin 75 mg subcutaneously five times per week for a median of 8.2 months until progression or complete response. 3/44 patients were secondarily accessible to local ablation or chemoembolisation. Primary endpoint was overall survival, secondary endpoint tumor response or progression-free survival. A multivariate Cox's regression model was used to identify variables affecting survival. Results Median survival was 11.5 months (95% CI 7.9–15.0 with a 1-, 2- and 3-year survival of 50%, 23% and 9%. In the univariate analysis, a low Child-Pugh-score (p = 0.01, a low score in the Okuda- and CLIP-classification (p Conclusion Outcome in our study rather depended on liver function and intrahepatic tumor growth (presence of liver cirrhosis and Okuda stage in addition to response to thymostimulin, while an invasive HCC phenotype had no influence in the multivariate analysis. Thymostimulin could therefore be considered a safe and promising candidate for palliative treatment in a selected target population with advanced hepatocellular carcinoma, in particular as component of a multimodal therapy concept. Trial registration Current Controlled Trials ISRCTN29319366.

  18. Hepatocellular carcinoma in situs inversus totalis-a case report

    Directory of Open Access Journals (Sweden)

    Thuingaren Sareo

    2014-03-01

    Full Text Available A 43-year old male presented with persistent discomfort and pain upper abdomen (epigastrium more on left side associated with fever on and off, along with fatigue and loss of appetite for the last four months. Physical examination revealed mass on left hypochondrium extending to epigastrium with mild distension of the abdomen. Imaging studies of the patient showed dextrocardia on chest x-ray  postero-anterior (PA view, thoracic and abdominal CT scan showed situs inversus totalis with multiple SOL (space occupying lesion in right lobe of liver with largest measuring 8x6 cm2 in the 4th segment. USG-guided FNAC of the mass showed features of hepatocellular carcinoma. Thereupon, hepatocellular carcinoma in situs inversus totalis was diagosed to this patient and was clinically staged as T3aN0M0. He was given sorafenib 400 mg orally twice daily with an advice to come for regular assessment every 4 week.Keywords: hepatocellular carcinoma, situs inversus totalis, case report

  19. Hepatectomy for Hepatocellular Carcinoma Complicated by Vasculitis Flare

    Directory of Open Access Journals (Sweden)

    Zeinab Abdi

    2010-01-01

    Full Text Available Background. The hepatitis C virus is a major cause of hepatocellular carcinoma. Extrahepatic manifestations of hepatitis C include mixed cryoglobulinemia which can result in ischemic damage to multiple organs. The management of these sequelae in posthepatectomy patients is unclear. Case Report. A 49-year-old male with hepatitis C was found to have a 4 cm hepatocellular carcinoma on surveillance imaging. He underwent portal vein embolization followed by hepatectomy. His postoperative course was complicated by the development of splenic infarcts, small bowel ischemia, skin lesions, and liver damage. Findings of elevated cryocrit and elevated rheumatoid factor suggested the diagnosis of cryoglobulin-related vasculitis. The patient improved on supportive care. Conclusion. Cryoglobulinemia is associated with hepatitis C and may complicate the care of this patient population. The treatment of cryoglobulinemia posthepatectomy patients is complicated by concerns over how medications may affect the regenerating liver. Steroids should be used with caution in this setting. Summary. Brief report of hepatectomy complicated by vasculitis in the context of hepatocellular carcinoma secondary to hepatitis C addresses the management of mixed cryoglobulinemia in post-hepatectomy patients.

  20. Hepatitis infections, aflatoxin and hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Pierre Hainaut

    2007-02-01

    Full Text Available

    The incidence rates of hepatocellular carcinoma (HCC show large geographic variations, globally reflecting the prevalence of two main aetiologic factors, hepatitis B (HBV and/or C (HCV virus infection and exposure to high levels of aflatoxin in the diet (Chen et al. 1997. The highest incidence rates are observed in regions where most of the population is exposed to both factors, such as in parts of eastern Asia and in sub-Saharan Africa (Parkin et al. 2001. These high incidences are consistent with the fact that HBV chronicity and exposure to aflatoxin have a multiplicative effect of risk for HCC. Depending on aetiology and geographic area, mutations in TP53 show striking differences in prevalence and pattern. In Europe and the US, where alcohol is a major risk factor in addition to viral infections, mutations occur in about 25% of HCC and show as much diversity in their type and codon position as in most other epithelial cancers. However, in high incidence areas such as Mozambique, Senegal, The Gambia (Africa and Qidong county (China, TP53 is mutated in over 50% of the cases and the vast majority of these mutations are a single missense, hotspot mutation at codon 249, AGG to AGT, resulting in the substitution of arginine into serine (249ser. This mutation is uncommon in regions where aflatoxin is not present at significant levels in the diet. In areas of intermediate exposure to aflatoxin, as for example in Thailand, the prevalence of the 249ser mutation is intermediate between high- and low-incidence areas. Thus, there is a dose-dependent relationship between exposure to aflatoxin, incidence of HCC and prevalence of 249ser mutation. Aflatoxins are toxic and carcinogenic metabolites produced by several varieties of molds, mainly Aspergillus flavus and Aspergillus parasiticum. These molds contaminate a wide range of traditional agricultural products in countries

  1. Serine protease HtrA1 expression in human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Feng Zhu; Lei Jin; Tian-Ping Luo; Guang-Hua Luo; Yan Tan; Xi-Hu Qin

    2010-01-01

    BACKGROUND: HtrA1, a serine protease, is down-regulated in various human solid tumors. Overexpression of HtrA1 in human cancer cells inhibits cell growth and proliferation in vitro and in vivo, suggesting its possible role as a tumor suppressor. METHODS: Immunohistochemistry was used to determine the expression of HtrA1 in 50 hepatocellular carcinoma specimens and adjacent liver tissues. The correlation between the expression of HtrA1 and the clinico-pathologic data were analyzed. RESULTS:  The levels of HtrA1 were lower in tumor tissues than in their adjacent liver tissues. Moreover, an inverse relationship was found between HtrA1 expression and the differentiation of hepatocellular carcinoma. Loss of HtrA1 was more frequently found in tumors in Edmondson grade III-IV, especially in those with venous invasion, compared to tumors in Edmondson grade I-II. Most importantly, patients with higher HtrA1 expression had a better survival rate. CONCLUSION: All these data suggest an important role of HtrA1 in hepatocellular carcinoma development and progression, which may be a new target for its treatment.

  2. Bufalin inhibits migration and invasion in human hepatocellular carcinoma SK-Hep1 cells through the inhibitions of NF-kB and matrix metalloproteinase-2/-9-signaling pathways.

    Science.gov (United States)

    Chen, Ya-Yin; Lu, Hsu-Feng; Hsu, Shu-Chun; Kuo, Chao-Lin; Chang, Shu-Jen; Lin, Jen-Jyh; Wu, Ping-Ping; Liu, Jia-You; Lee, Ching-Hsiao; Chung, Jing-Gung; Chang, Jin-Biou

    2015-01-01

    Metastasis plays an important role in mortality of cancer patients. Migration and invasion are the major characteristics of tumor metastasis. The induction of matrix metalloproteinases (MMPs) such as MMP-2 and -9 are particularly important for the invasiveness of various cancer cells. Bufalin, a class of toxic steroids, was purified from the skin glands of Bufo gargarizans or Bufo melanostictus; it is known to inhibit proliferation of human cancer cells. In this study, we investigated the antiinvasive mechanisms of bufalin in the human hepatocellular cancer cell line SK-Hep1. Bufalin significantly reduced serum-induced cell invasion and migration. Furthermore, bufalin markedly inhibited MMP-2 and -9 activity, mRNA expression and protein levels in SK-Hep1 cells. Bufalin attenuated phosphoinisitide-3-kinase (PI3K) and phosphorylation of AKT which was associated with reduced levels of nuclear factor kappa B (NF-κB). Bufalin also suppressed protein levels of FAK and Rho A, VEGF, MEKK3, MKK7, and uPA and it diminished NF-κB translocation. Based on these observations, we propose that bufalin is acts as an antiinvasive agent by inhibiting MMP-2 and -9 and involving PI3K/AKT and NF-κB pathways. Bufalin is a potential therapeutic agent that may have efficacy in preventing the invasion and metastasis of malignant liver tumors.

  3. Primary study of leptin and human hepatocellular carcinoma in vitro

    Institute of Scientific and Technical Information of China (English)

    Jing Zhou; Wei Lei; Lei Shen; He-Sheng Luo; Zhi-Xiang Shen

    2008-01-01

    AIM: To investigate the expression level and effects of leptin in human hepatocellular carcinoma cells in vitro and to explore the correlation between them.METHODS: Human hepatocellular carcinoma cell line HepG2 was cultured in vitro, and (the expression level)mRNA of leptin and leptin receptors in HepG2 were assessed using reverse transcription polymerase chain reaction (RT-PCR). Effects of different concentrations of leptin (50 ng/mL, 100 ng/mL, 200 ng/mL) on HepG2 were detected with colorimetric assay by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) after incubation periods of 24 h, 48 h,and 72 h. Flow cytometry was performed to assess cell cycle progression of different concentrations of leptin as stated above after each 24 h incubation period.RESULTS: mRNA of leptin and leptin receptors (including short and long isoforms) were expressed in HepG2.The 72 h incubation of leptin at different concentrations (50 ng/mL, 100 ng/mL, 200 ng/mL) promoted proliferation of HepG2 in a concentration- and timedependent manner. The experimental group shows significant statistical differences when compared to the controlled group which contained 0 ng/mL of leptin. As the concentration of leptin increases, significant fewer cells were detected in G0-G1 phase and more cells in S and G2-M phases.CONCLUSION: Leptin and leptin receptor are simultaneously expressed in human hepatocellular carcinoma cell line HepG2. Addition of leptin (O ng/mL200 ng/mL) in 72 h periods indicated there is a concentration- and time-dependent correlation in the stimulation of HepG2 cell proliferation. The effect of proliferation by leptin is due to promotion of DNA synthesis and enhancement of mitotic activity. The relationship between leptin and human hepatocellular carcinoma cells might indicate that adipokine could be associated with the progression of human hepatocellular carcinoma.

  4. Albumin Suppresses Human Hepatocellular Carcinoma Proliferation and the Cell Cycle

    Directory of Open Access Journals (Sweden)

    Shunsuke Nojiri

    2014-03-01

    Full Text Available Many investigations have revealed that a low recurrence rate of hepatocellular carcinoma (HCC is associated with high serum albumin levels in patients; therefore, high levels of serum albumin are a major indicator of a favorable prognosis. However, the mechanism inhibiting the proliferation of HCC has not yet been elucidated, so we investigated the effect of serum albumin on HCC cell proliferation. Hep3B was cultured in MEM with no serum or containing 5 g/dL human albumin. As control samples, Prionex was added to generate the same osmotic pressure as albumin. After 24-h incubation, the expressions of α-fetoprotein (AFP, p53, p21, and p57 were evaluated with real-time PCR using total RNA extracted from the liver. Protein expressions and the phosphorylation of Rb (retinoblastoma were determined by Western blot analysis using total protein extracted from the liver. For flow cytometric analysis of the cell cycle, FACS analysis was performed. The percentages of cell cycle distribution were evaluated by PI staining, and all samples were analyzed employing FACScalibur (BD with appropriate software (ModFit LT; BD. The cell proliferation assay was performed by counting cells with using a Scepter handy automated cell counter (Millipore. The mRNA levels of AFP relative to Alb(−: Alb(−, Alb(+, and Prionex, were 1, 0.7 ± 0.2 (p < 0.001 for Alb(−, and 1 ± 0.3, respectively. The mRNA levels of p21 were 1, 1.58 ± 0.4 (p = 0.007 for Alb(− and p = 0.004 for Prionex, and 0.8 ± 0.2, respectively. The mRNA levels of p57 were 1, 4.4 ± 1.4 (p = 0.002 for Alb(− and Prionex, and 1.0 ± 0.1, respectively. The protein expression levels of Rb were similar in all culture media. The phosphorylation of P807/811 and P780 of Rb protein was reduced in Alb(+. More cells in the G0/G1 phase and fewer cells in S and G2/M phases were obtained in Alb(+ than in Alb(− (G0/G1: 60.9%, 67.7%, 61.5%; G2/M: 16.5%, 13.1%, 15.6%; S: 22.6%, 19.2%, 23.0%, Alb(−, Alb

  5. Hepatocellular Carcinoma in Tyrosinemia Type 1 Without Clear Increase of AFP

    NARCIS (Netherlands)

    van Ginkel, Willem G.; Gouw, Annette S. H.; van der Jagt, Eric J.; de Jong, Koert P.; Verkade, Henkjan J.; van Spronsen, Francjan J.

    2015-01-01

    Patients with hereditary tyrosinemia type 1 have an elevated risk of developing hepatocellular carcinoma, especially if initiation of treatment with 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione is delayed. Hepatocellular carcinoma can usually be suspected when there are increased alpha

  6. Co-localization of the heat shock protein and human immunoglobulin G in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    DUAN Chun-guang; LIU Yan-fang; LI Kai-nan; YU Lu; CUI Ji-hong; LI Jing; YANG Shou-jing

    2005-01-01

    @@ Elevated levels of serum immunoglobulin observed in patients with cancers of epithelial origin, including carcinomas of breast, colon, and liver1,2 have been interpreted as humoral responses of host to cancer growth.3 Recently, Qiu et al4 described in detail that human cancers of epithelial origin, including carcinomas of breast, colon, liver, lung, established epithelial cancer lines, produce immunoglobulin G (IgG) in their cytoplasm. Under normal conditions, heat shock proteins (HSPs) have multiple cellular functions, such as folding and translocating newly synthesized proteins. When a cell is injured or under stress, HSPs refold damaged protein or facilitate degradation of proteins. In most cancers, heat shock proteins can capture tumour specific peptide to inhibit the growth of cancer. This study demonstrated that human IgG and HSPs are co-localized in hepatocellular carcinoma.

  7. Transarterial chemoembolization for huge hepatocellular carcinoma with diameter over ten centimeters: a large cohort study.

    Science.gov (United States)

    Xue, Tongchun; Le, Fan; Chen, Rongxin; Xie, Xiaoying; Zhang, Lan; Ge, Ningling; Chen, Yi; Wang, Yanhong; Zhang, Boheng; Ye, Shenglong; Ren, Zhenggang

    2015-03-01

    Patients with huge hepatocellular carcinoma >10 cm in diameter represent a special subgroup for treatment. To date, there are few data and little consensus on treatment strategies for huge hepatocellular carcinoma. In this study, we summarized the effects and safety of transarterial chemoembolization for huge hepatocellular carcinoma. A retrospective study was performed based on a large cohort of patients (n = 511) with huge hepatocellular carcinoma who underwent serial transarterial chemoembolization between January 2008 to December 2011 and were followed up until March 2013. We found median survival time was 6.5 months. On multivariate analysis, Child-Pugh class (A versus B) (p huge hepatocellular carcinoma and is recommended as a component of combination therapy. In addition, patients with good liver function and low alpha-fetoprotein levels may acquire greater survival benefits from transarterial chemoembolization.

  8. A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Dalhoff, K; Dancey, J; Astrup, L

    2003-01-01

    growth in cancer cell lines and in vivo. The vitamin D receptor is expressed in hepatocytes and more abundantly in HCC cells. In total, 56 patients with inoperable advanced HCC were included in an uncontrolled study of oral Seocalcitol treatment for up to 1 year (with possible extension for responders......Hepatocellular carcinoma (HCC) is a common malignant tumour, which has a poor prognosis. Surgical resection can be curative but most patients are inoperable and most chemotherapy agents have minimal activity in this disease. Seocalcitol, a vitamin D analogue, induces differentiation and inhibits...

  9. Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients

    Science.gov (United States)

    Jiang, Peiyong; Chan, Carol W. M.; Chan, K. C. Allen; Cheng, Suk Hang; Wong, John; Wong, Vincent Wai-Sun; Wong, Grace L. H.; Chan, Stephen L.; Mok, Tony S. K.; Chan, Henry L. Y.; Lai, Paul B. S.; Chiu, Rossa W. K.; Lo, Y. M. Dennis

    2015-01-01

    The analysis of tumor-derived circulating cell-free DNA opens up new possibilities for performing liquid biopsies for the assessment of solid tumors. Although its clinical potential has been increasingly recognized, many aspects of the biological characteristics of tumor-derived cell-free DNA remain unclear. With respect to the size profile of such plasma DNA molecules, a number of studies reported the finding of increased integrity of tumor-derived plasma DNA, whereas others found evidence to suggest that plasma DNA molecules released by tumors might be shorter. Here, we performed a detailed analysis of the size profiles of plasma DNA in 90 patients with hepatocellular carcinoma, 67 with chronic hepatitis B, 36 with hepatitis B-associated cirrhosis, and 32 healthy controls. We used massively parallel sequencing to achieve plasma DNA size measurement at single-base resolution and in a genome-wide manner. Tumor-derived plasma DNA molecules were further identified with the use of chromosome arm-level z-score analysis (CAZA), which facilitated the studying of their specific size profiles. We showed that populations of aberrantly short and long DNA molecules existed in the plasma of patients with hepatocellular carcinoma. The short ones preferentially carried the tumor-associated copy number aberrations. We further showed that there were elevated amounts of plasma mitochondrial DNA in the plasma of hepatocellular carcinoma patients. Such molecules were much shorter than the nuclear DNA in plasma. These results have improved our understanding of the size profile of tumor-derived circulating cell-free DNA and might further enhance our ability to use plasma DNA as a molecular diagnostic tool. PMID:25646427

  10. Hepatocellular carcinoma and the risk of occupational exposure

    Science.gov (United States)

    Rapisarda, Venerando; Loreto, Carla; Malaguarnera, Michele; Ardiri, Annalisa; Proiti, Maria; Rigano, Giuseppe; Frazzetto, Evelise; Ruggeri, Maria Irene; Malaguarnera, Giulia; Bertino, Nicoletta; Malaguarnera, Mariano; Catania, Vito Emanuele; Di Carlo, Isidoro; Toro, Adriana; Bertino, Emanuele; Mangano, Dario; Bertino, Gaetano

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The main risk factors for HCC are alcoholism, hepatitis B virus, hepatitis C virus, nonalcoholic steatohepatitis, obesity, type 2 diabetes, cirrhosis, aflatoxin, hemochromatosis, Wilson’s disease and hemophilia. Occupational exposure to chemicals is another risk factor for HCC. Often the relationship between occupational risk and HCC is unclear and the reports are fragmented and inconsistent. This review aims to summarize the current knowledge regarding the association of infective and non-infective occupational risk exposure and HCC in order to encourage further research and draw attention to this global occupational public health problem. PMID:27168870

  11. Research advances in Hedgehog signaling pathway in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    LIU Jia

    2015-02-01

    Full Text Available Hedgehog (Hh signaling pathway is present in many animals and plays an important role in regulating embryonic development and differentiation. Aberrant activation of Hh signaling contributes to the pathogenesis of many malignancies. Recent studies have shown that dysregulated Hh signaling pathway participates in the tumorigenesis, tumor invasion, and metastasis of hepatocellular carcinoma (HCC. Investigation of the relationship between Hh signaling pathway and HCC will help elucidate the molecular mechanism of pathogenesis of HCC and provide a new insight into the development of novel anticancer therapy and therapeutic target.

  12. Evolution of systemic therapy of advanced hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Thomas Yau; Pierre Chan; Richard Epstein; Ronnie T Poon

    2008-01-01

    Hepatocellular carcinoma (HCC) commonly occurs in hepatitis B endemic areas, especially in Asian countries. HCC is highly refractory to cytotoxic chemotherapy. This resistance is partly related to its tumor biology, pharmacokinetic properties, and both intrinsic and acquired drug resistance. There is no convincing evidence thus far that systemic chemotherapy improves overall survival in advanced HCC patients.Other systemic approaches, such as hormonal therapy and immunotherapy, have also disappointing results. Recently, encouraging results have been shown in using sorafenib in the treatment of advanced HCC patients. In this review, we concisely summarize the evolution of developments in the systemic therapy of advanced HCC.

  13. Usefulness of MRI in diagnosis of hepatocellular carcinoma (HCC)

    Energy Technology Data Exchange (ETDEWEB)

    Usuki, Noriaki; Kawabe, Jouji; Nishikawa, Minori; Fukuda, Haruyuki; Saiwai, Shigeo; Nakajima, Hideyuki; Miyamoto, Takeshi; Kudoh, Masatoshi (Kobe General City Hospital (Japan))

    1992-06-01

    Sixty-six cases of histologically proven hepatocellular carcinomas (HCC) were studied by MRI. Detectability was better by MRI than by CT, especially in the tumor under 2 cm in diameter. The capsule was detected in all cases of HCC over 3 cm in diameter. The capsule was able to be diagnosed only by dynamic MRI study in some cases. High intensity on the T1-weighted image and iso or low intensity on the T2-weighted image suggested that the nodule was adenomatous hyperplasi (AH) or well differentiated HCC. MRI is concluded to be an essential modality in the diagnosis of HCC. (author).

  14. Resection of a giant hepatocellular carcinoma weighing over ten kilograms

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The authors report a giant hepatocellular carcinoma(HCC)with a diameter over 30 cm and weight over 10 kg that was resected completely.A 62-year-old man was admitted because of continuous abdominal uplift.A computed tomography scan demonstrated that the entire abdomen was filled with a giant tumor containing both cystic and solid components with a size of 29 cm×22 cm.The huge tumor was successfully resected without any complication,such as massive hemorrhage or visceral injuries.The size and weight of the tu...

  15. Dysregulated serum response factor triggers formation of hepatocellular carcinoma.

    OpenAIRE

    Ohrnberger, Stefan; Thavamani, Abhishek; Braeuning, Albert; Daniel B. Lipka; Kirilov, Milen; Geffers, Robert; Authenrieth, Stella E; Römer, Michael; Zell, Andreas; Bonin, Michael; Schwarz, Michael; Schütz, Günther; Schirmacher, Peter; Plass, Christoph; Longerich, Thomas

    2015-01-01

    The ubiquitously expressed transcriptional regulator serum response factor (SRF) is controlled by both Ras/MAPK (mitogen-activated protein kinase) and Rho/actin signaling pathways, which are frequently activated in hepatocellular carcinoma (HCC). We generated SRF-VP16iHep mice, which conditionally express constitutively active SRF-VP16 in hepatocytes, thereby controlling subsets of both Ras/MAPK- and Rho/actin-stimulated target genes. All SRF-VP16iHep mice develop hyperproliferative liver nod...

  16. Hepatocellular carcinoma complicating cystic fibrosis related liver disease.

    LENUS (Irish Health Repository)

    O'Donnell, D H

    2012-02-01

    Early diagnosis and treatment of the respiratory and gastrointestinal complications of cystic fibrosis (CF) have led to improved survival with many patients living beyond the fourth decade. Along with this increased life expectancy is the risk of further disease associated with the chronic manifestations of their condition. We report a patient with documented CF related liver disease for which he was under routine surveillance that presented with histologically proven hepatocellular carcinoma (HCC). It is important that physicians are aware of this association as increased vigilance may lead to earlier diagnosis and perhaps, a better outcome.

  17. Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma

    DEFF Research Database (Denmark)

    Chaisaingmongkol, Jittiporn; Budhu, Anuradha; Dang, Hien

    2017-01-01

    Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are clinically disparate primary liver cancers with etiological and biological heterogeneity. We identified common molecular subtypes linked to similar prognosis among 199 Thai ICC and HCC patients through systems integration...... of genomics, transcriptomics, and metabolomics. While ICC and HCC share recurrently mutated genes, including TP53, ARID1A, and ARID2, mitotic checkpoint anomalies distinguish the C1 subtype with key drivers PLK1 and ECT2, whereas the C2 subtype is linked to obesity, T cell infiltration, and bile acid...

  18. Nonalcoholic Fatty liver disease, diabetes, obesity, and hepatocellular carcinoma.

    Science.gov (United States)

    Noureddin, Mazen; Rinella, Mary E

    2015-05-01

    Diabetes and obesity are associated with nonalcoholic fatty liver disease (NAFLD) and an increased incidence of hepatocellular carcinoma (HCC). NAFLD is the commonest cause of chronic liver disease. HCC can develop in NAFLD patients even without cirrhosis, suggesting an association between the metabolic process and HCC and raising a concern that many cancers could be missed given high NAFLD prevalence and screening limitations. The increasing prevalence of these conditions and lack of effective treatments necessitate a better understanding of their connection. This article defines the known interrelationships and common pathways between NAFLD, diabetes, obesity and HCC and possible chemoprevention strategies. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Functional Roles and Therapeutic Applications of Exosomes in Hepatocellular Carcinoma.

    Science.gov (United States)

    Santangelo, Laura; Battistelli, Cecilia; Montaldo, Claudia; Citarella, Franca; Strippoli, Raffaele; Cicchini, Carla

    2017-01-01

    Exosomes are important in intercellular communication. They assure the horizontal transfer of specific functional contents (i.e., proteins, lipids, RNA molecules, and circulating DNA) from donor to recipient cells. Notably, tumor-derived exosomes (TDEs) appear to be an important vehicle of specific signals in cancer, impacting on tumor growth and metastasis. Recent researches point to the characterization of exosomes in Hepatocellular Carcinoma (HCC), the major adult liver malignancy. In this review, we summarize current findings on HCC exosomes, focusing on the identification of noncoding RNAs as exosome-enriched functional regulators and new potential biomarkers. The great potential of exosomes in future HCC diagnostic and therapeutic approaches is underlined.

  20. Laser ablation of hepatocellular carcinoma-A review

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    A wide range of local thermal ablative therapies have been developed in the treatment of non resectable hepatocellular carcinoma (HCC) in the last decade. Laser ablation (LA) and radiofrequency ablation (RFA) are the two most widely used of these. This article provides an up to date overview of the role of laser ablation in the local treatment of HCC. General principles, technique, image guidance and patient selection are discussed. A review of published data on treatment efficacy, long term outcome and complication rates of laser ablation is included and comparison with RFA made. The role of laser ablation in combination with transcatheter arterial chemoembolisation is also discussed.

  1. Surgical resection for hepatocellular carcinoma in pregnancy: A case report

    Directory of Open Access Journals (Sweden)

    Chih-Chiang Hung

    2012-07-01

    Full Text Available Hepatocellular carcinoma (HCC occurring in pregnancy is very rare. The prognosis is usually poor because of unclear clinical presentation. A 30-year-old woman who suffered from HCC during pregnancy underwent hepatectomy twice, and resection for pulmonary metastasis once. A healthy infant was delivered after the first hepatectomy. Currently, she remains disease free 55 months after the second hepatectomy and 39 months after pulmonary metastatectomy. Moreover, she had another healthy infant 37 months after pulmonary metastatectomy. Aggressive resection of recurrent HCC may prolong life, and pregnancy should not alter the treatment strategy for HCC.

  2. Local recurrence of hepatocellular carcinoma after radiofrequency ablation

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    A 51-year-old Chinese male with a 20-year history of hepatitis B was diagnosed with hepatocellular carcinoma in the right anterior portion of the liver, sized 3.5 cm × 3.2 cm, and was treated with radiofrequency ablation (RFA) on December 18, 2001. The patient did not receive antiviral therapy for hepatitis B virus after RFA. The treated lesion reduced gradually and reached its minimum size of 1.7 cm × 1.5 cm seven years later on November 18, 2008. However computed tomography findings revealed that a recurr...

  3. The role of cyclin E1 in hepatocellular carcinoma

    OpenAIRE

    Chan, Yan-yan; 陳茵茵

    2014-01-01

    Hepatocellular carcinoma (HCC) accounts for 70-85% of liver cancer, which is the sixth most common cancer in the world. Prognosis of HCC is dismal with little chance of complete recovery after diagnosis. It is of essence to discover the key molecules involved in the tumor progression. This could help earlier detection of HCC and establish targeted molecular therapies. Cyclin E1 (CCNE1) is a cyclin molecule responsible for the transition from G1 to S phase of the cell cycle and is often dysreg...

  4. The Influence of Nano-apatite on c-myc and p53 Gene in the Hepatocellular Carcinoma

    Institute of Scientific and Technical Information of China (English)

    CHEN Jun; CAO Xianying; LI Shipu; HAN Yingchao; ZHANG Ran

    2005-01-01

    The influence mechanism of the nano-apatite on the human hepatocellular carcinoma in vitro was investigated. Using the homogeneous precipitation method, the nano-apatite was synthesized at room temperature, and it was characterized with transmission electron microscopy (TEM) and the Zataplus. The influence on the expression of the c-myc and p53 gene in the human hepatocellular carcinoma cell lines were tested with the TEM and hybridization in situ. The TEM and the Zataplus analyses show that the nano-apatite is distributed homogenously in size and needle-shaped sizes, which ranges from 67.5 nm to 88.3 nm. It is found that the nano-apatitet increases the volume of the human hepatocellular carcinoma cells, makes extensive cytoplasmic vacuolization, the mitochondria swelling, chromatin in nucleus dispersed partially and condensed around the nuclear membranes.The interspace in nuclear membranes were separated and even the cytoplasm dissolved. It is also found that the expression of the c-myc gene is inhibited, but the p53 is enhanced. The experimental results demonstrate that the nano-apatite enables the oncosis of the human hepatocellular carcinoma cells by down-regulation of the expression of the c-myc and up-regulation of the expression of the p53 in vitro.

  5. Interon-gamma Enhances the Antitumor Effect of All-trans Retinoic Acid on Hepatocellular Carcinoma Cells by Inhibiting the Expression of Nuclear Factor-kappaB

    Institute of Scientific and Technical Information of China (English)

    YIN Yuan-qin; WANG Xiao-hua; MA Ping; FU Liye; HANG Tao; WANG Yang

    2008-01-01

    Objective:To explore the combination effects of all-trans retinoic acid(ATRA)with interferon-gamma(IFN-γ)on human hepatocarcinoma cell line SMMC-7721 and the mechanism of action.Methods:SMMC-7721 cells were divided into treated group and control group.The cells were treated with ATRA or ATRA+IFN-γ in the former and added with PBS in the latter.The inhibition rate of SMMC-7721 cell proliferation was detected by MTT,the cell change in morphology was observed by electron microscope.The apoptosis was detected by flow cytometry and the expression changes of nuclear factor-kappaB(NF-κB)was analyzed by Western blotting when the SMMC-7721 cells were treated with ATRA and IFN-γ.Results:The SMMC-7721 cell proliferation was suppressed and apoptosis was induced after the cells were treated with ATRA treatment,and these effects were enhanced when ATRA was combined with IFN-γ.The expression of NF-κB was reduced after SMMC-7721 cell was treated with ATRA,and reduced significantly when the cells were treated with the combination of ATRA and IFN-γ.Conclusion:IFN-γ can enhance the inhibiting effects of ATRA on cell proliferation and inducing apoptosis on SMMC-7721 cell and these effects might be mediated by inhibiting the expression of NF-κB.

  6. Anatomic pathology of hepatocellular carcinoma: histopathology using classic and new diagnostic tools.

    Science.gov (United States)

    Pittman, Meredith E; Brunt, Elizabeth M

    2015-05-01

    Hepatocellular carcinoma can be diagnosed on a needle biopsy of the liver; however, uncertainty may arise because of the inherent complexity of liver histology. This article aims to provide practicing pathologists with tools for the approach to mass-directed liver biopsies clinically concerning for hepatocellular carcinoma. The examination of routine hematoxylin-eosin stains and the use of ancillary histochemical and immunohistochemical stains are discussed. Sections reviewing liver carcinoma with biphenotypic differentiation and the challenge of dysplastic nodules are included.

  7. Spontaneous rupture of multifocal hepatocellular carcinoma: case report

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    Özen Ö

    2015-08-01

    Full Text Available Özkan Özen, Alptekin Tosun, Çiğdem Akgül Department of Radiology, Faculty of Medicine, Giresun University, Giresun, Turkey Abstract: Hemoperitoneum due to nontraumatic liver rupture is rare. The most common cause of nontraumatic rupture of the liver is hepatocellular carcinoma (HCC. The other causes of nontraumatic liver ruptures are peliosis hepatis, polyarteritis nodosa, systemic lupus erythematosus, preeclampsia, metastatic carcinoma, and other primary liver tumors. In this report, we present the computed tomography findings of spontaneous liver rupture in a 52-year-old male patient due to multifocal HCC, with the diagnosis proven by surgical specimen. Keywords: computed tomography, hemoperitoneum, liver, nontraumatic liver rupture

  8. Early steroid withdrawal after liver transplantation for hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To evaluate the impact of early steroid withdrawal on the incidence of rejection, tumor recurrence and complications after liver transplantation for advancedstage hepatocellular carcinoma.METHODS: Fifty-four patients underwent liver transplantation for advanced-stage hepatocellular carcinoma from April 2003 to June 2005. These cases were divided into a steroid-withdrawal group (group A, n = 28) and a steroid-maintenance group (group B,n = 26). In group A, steroid was withdrawn 3 mo after transplantation. In group B, steroid was continuously used postoperatively. The incidence of rejection, 6-mo and 1-year recurrence rate of carcinoma, 1-year survival rate, mean serum tacrolimus trough level, and liver and kidney function were compared between the two groups.RESULTS: In the two groups, no statistical difference was observed in the incidence of rejection (14.3 vs 11.5%, P > 0.05), mean serum tacrolimus trough levels (6.9 ± 1.4 vs 7.1 ± 1.1 μg/L, P > 0.05), liver and kidney function after 6 mo [alanine aminotransferase (ALT):533 ± 183 vs 617 ± 217 nka/L, P > 0.05; creatinine:66 ± 18 vs 71 ± 19 μmol/L, P > 0.05], 6-mo recurrence rate of carcinoma (25.0 vs 42.3%, P > 0.05), and 1-year survival rate (64.2 vs 46.1%, P > 0.05). The 1-year tumor recurrence rate (39.2 vs 69.2%, P < 0.05), serum cholesterol level (3.9 ± 1.8 vs 5.9 ± 2.6 mmol/L, P < 0.01)and fasting blood sugar (5.1 ± 2.1 vs 8.9 ± 3.6 mmol/L,P < 0.01) were significantly different. These were lower in the steroid-withdrawal group than in the steroidmaintenance group.CONCLUSION: Early steroid withdrawal was safe after liver transprantation in patients with advanced-stage hepatocellular carcinoma. When steroids were withdrawn 3 mo post-operation, the incidence of rejection did not increase, and there was no demand to maintain tacrolimus at a high level. In contrast, the tumor recurrence rate and the potential of adverse effects decreased significantly. This may have led to an

  9. Early steroid withdrawal after liver transplantation for hepatocellular carcinoma

    Science.gov (United States)

    Chen, Zhi-Shui; He, Fan; Zeng, Fan-Jun; Jiang, Ji-Pin; Du, Dun-Feng; Liu, Bin

    2007-01-01

    AIM: To evaluate the impact of early steroid withdrawal on the incidence of rejection, tumor recurrence and complications after liver transplantation for advanced-stage hepatocellular carcinoma. METHODS: Fifty-four patients underwent liver transplantation for advanced-stage hepatocellular carcinoma from April 2003 to June 2005. These cases were divided into a steroid-withdrawal group (group A, n = 28) and a steroid-maintenance group (group B, n = 26). In group A, steroid was withdrawn 3 mo after transplantation. In group B, steroid was continuously used postoperatively. The incidence of rejection, 6-mo and 1-year recurrence rate of carcinoma, 1-year survival rate, mean serum tacrolimus trough level, and liver and kidney function were compared between the two groups. RESULTS: In the two groups, no statistical difference was observed in the incidence of rejection (14.3 vs 11.5%, P > 0.05), mean serum tacrolimus trough levels (6.9 ± 1.4 vs 7.1 ± 1.1 μg/L, P > 0.05), liver and kidney function after 6 mo [alanine aminotransferase (ALT): 533 ± 183 vs 617 ± 217 nka/L, P > 0.05; creatinine: 66 ± 18 vs 71 ± 19 μmol/L, P > 0.05], 6-mo recurrence rate of carcinoma (25.0 vs 42.3%, P > 0.05), and 1-year survival rate (64.2 vs 46.1%, P > 0.05). The 1-year tumor recurrence rate (39.2 vs 69.2%, P < 0.05), serum cholesterol level (3.9 ± 1.8 vs 5.9 ± 2.6 mmol/L, P < 0.01) and fasting blood sugar (5.1 ± 2.1 vs 8.9 ± 3.6 mmol/L, P < 0.01) were significantly different. These were lower in the steroid-withdrawal group than in the steroid-maintenance group. CONCLUSION: Early steroid withdrawal was safe after liver transplantation in patients with advanced-stage hepatocellular carcinoma. When steroids were withdrawn 3 mo post-operation, the incidence of rejection did not increase, and there was no demand to maintain tacrolimus at a high level. In contrast, the tumor recurrence rate and the potential of adverse effects decreased significantly. This may have led to an increase

  10. Proteomic Studies of Cholangiocarcinoma and Hepatocellular Carcinoma Cell Secretomes

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    Chantragan Srisomsap

    2010-01-01

    Full Text Available Cholangiocarcinoma (CCA and hepatocellular carcinoma (HCC occur with relatively high incidence in Thailand. The secretome, proteins secreted from cancer cells, are potentially useful as biomarkers of the diseases. Proteomic analysis was performed on the secreted proteins of cholangiocarcinoma (HuCCA-1 and hepatocellular carcinoma (HCC-S102, HepG2, SK-Hep-1, and Alexander cell lines. The secretomes of the five cancer cell lines were analyzed by SDS-PAGE combined with LC/MS/MS. Sixty-eight proteins were found to be expressed only in HuCCA-1. Examples include neutrophil gelatinase-associated lipocalin (lipocalin 2, laminin 5 beta 3, cathepsin D precursor, desmoplakin, annexin IV variant, and annexin A5. Immunoblotting was used to confirm the presence of lipocalin 2 in conditioned media and cell lysate of 5 cell lines. The results showed that lipocalin 2 was a secreted protein which is expressed only in the conditioned media of the cholangiocarcinoma cell line. Study of lipocalin 2 expression in different types of cancer and normal tissues from cholangiocarcinoma patients showed that lipocalin 2 was expressed only in the cancer tissues. We suggest that lipocalin 2 may be a potential biomarker for cholangiocarcinoma.

  11. Nanosecond pulsed electric field ablation of hepatocellular carcinoma.

    Science.gov (United States)

    Beebe, Stephen J; Chen, Xinhua; Liu, Jie A; Schoenbach, Karl H

    2011-01-01

    Hepatocellular carcinoma often evades effective therapy and recurrences are frequent. Recently, nanosecond pulsed electric field (nsPEF) ablation using pulse power technology has emerged as a local-regional, non-thermal, and non-drug therapy for skin cancers. In the studies reported here we use nsPEFs to ablate murine, rat and human HCCs in vitro and an ectopic murine Hepa 1-6 HCC in vivo. Using pulses with 60 or 300 ns and electric fields as high as 60 kV/cm, murine Hepa 1-6, rat N1S1 and human HepG2 HCC are readily eliminated with changes in caspase-3 activity. Interestingly caspase activities increase in the mouse and human model and decrease in the rat model as electric field strengths are increased. In vivo, while sham treated control mice survived an average of 15 days after injection and before humane euthanasia, Hepa 1-6 tumors were eliminated for longer than 50 days with 3 treatments using one hundred pulses with 100 ns at 55 kV/cm. Survival was 40% in mice treated with 30 ns pulses at 55 kV/cm. This study demonstrates that nsPEF ablation is not limited to effectively treating skin cancers and provides a rationale for treating orthotopic hepatocellular carcinoma in pre-clinical applications and ultimately in clinical trials.

  12. Histone deacetylase inhibitors for treatment of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Danila CORADINI; Annalisa SPERANZA

    2005-01-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers in the world.Surgical resection has been considered the optimal treatment approach, but only a small proportion of patients are suitable candidates for surgery, and the relapse rate is high. Approaches to prevent recurrence, including chemoemboliza-tion before and adjuvant therapy after surgery, have proven to have a limited benefit;liver transplantation is successful in treating limited-stage HCC because only a minority of patients qualify for transplantation. Therefore, new therapeutic strategies are urgently needed. Because in addition to the classical genetic mechanisms of deletion or inactivating point mutations, epigenetic alterations, such as hyperacetylation of the chromatin-associated histones (responsible for gene silencing), are believed to be involved in the development and progression of HCC, novel compounds endowed with a histone deacetylase (HDAC) inhibitory activity are an attractive therapeutic approach. In particular, pre-clinical results obtained using HA-But, an HDAC inhibitor in which butyric acid residues are esterified to a hyaluronic acid backbone and characterized by a high affinity for the membrane receptor CD44, indicated that this class of compounds may represent a promising approach for hepatocellular carcinoma treatment.

  13. Hepatitis B virus infection and the risk of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Ya-Jun Tan

    2011-01-01

    Epidemiological studies have provided overwhelming evidence for a causal role of chronic hepatitis B virus (HBV) infection in the development of hepatocellular carcinoma (HCC). However, the pathogenesis of HBV infection and carcinogenesis of HBV-associated HCC are still elusive. This review will summarize the current knowledge on the mechanisms involved in HBV-related liver carcinogenesis. The role of HBV in tumor formation appears to be complex, and may involve both direct and indirect mechanisms. Integration of HBV DNA into the host genome occurs at early steps of clonal tumor expansion, and it has been shown to enhance the host chromosomal instability, leading to large inverted duplications, deletions and chromosomal translocations. It has been shown that the rate of chromosomal alterations is increased significantly in HBV-related tumors. Prolonged expression of the viral regulatory HBV x protein may contribute to regulating cellular transcription, protein degradation, proliferation, and apoptotic signaling pathways, and it plays a critical role in the development of hepatocellular carcinoma.

  14. Spontaneous regression of a large hepatocellular carcinoma: case report

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    Alqutub, Adel

    2011-01-01

    Full Text Available The prognosis of untreated advanced hepatocellular carcinoma (HCC is grim with a median survival of less than 6 months. Spontaneous regression of HCC has been defined as the disappearance of the hepatic lesions in the absence of any specific therapy. The spontaneous regression of a very large HCC is very rare and limited data is available in the English literature. We describe spontaneous regression of hepatocellular carcinoma in a 65-year-old male who presented to our clinic with vague abdominal pain and weight loss of two months duration. He was found to have multiple hepatic lesions with elevation of serum alpha-fetoprotein (AFP level to 6,500 µg/L (normal <20 µg/L. Computed tomography revealed advanced HCC replacing almost 80% of the right hepatic lobe. Without any intervention the patient showed gradual improvement over a period of few months. Follow-up CT scan revealed disappearance of hepatic lesions with progressive decline of AFP levels to normal. Various mechanisms have been postulated to explain this rare phenomenon, but the exact mechanism remains a mystery.

  15. Infrequent microsatellite instability mutator phenotype in Chinese hepatocellular carcinomas

    Institute of Scientific and Technical Information of China (English)

    方丽; 房殿春; 汪荣泉; 杨仕明; 吴凯

    2003-01-01

    Objective:In order to elucidate the molecular mechanisms that might be responsible for hepatocarcinogenesis,we examined microsatellite instability(MSI),mismatch repair gene hMLH1 mutation and methylation in hepatocellular carcinoma.Methods:Fifty-two cases of surgically resected sporadic hepatocellular carcinoma(HCC)were studied.hMLH1 mutation was examined by two-dimensional electrophoresis and DNA sequencing; hMLH1 methylation was determined by methylation-specific PCR(MSP); and MSI at BAT26 was analyzed by PCR-based methods.Results:MSI at BAT26 was found in 3 of 52 cases(5.8%)of the tumors analyzed.No hMLH1 mutation or hypermethylation was found in these 52 cancerous tissues.No correlation existed between MSI and clinico-pathological characteristics of the patients.Conclusion:Our results suggest that MSI at BAT26 is rarely associated with carcinogenesis of chinese HCC.The genesis of sporadic HCC may occur in an alternative pathway that is probably different from MSI pathway.

  16. Vasculogenic mimicry in hepatocellular carcinoma contributes to portal vein invasion.

    Science.gov (United States)

    Jue, Chen; Zhifeng, Wu; Zhisheng, Zhang; Lin, Cui; Yayun, Qian; Feng, Jin; Hao, Gu; Shintaro, Ishikawa; Hisamitsu, Tadashi; Shiyu, Guo; Yanqing, Liu

    2016-11-22

    Portal vein invasion (PVI) is common in hepatocellular carcinoma (HCC) and largely contributes to tumor recurrence after radical tumor resection or liver transplantation. Vasculogenic mimicry (VM) was an independent vascular system lined with tumor cells and associated with poor prognosis of HCC. The present study was conducted to evaluate the relationship between VM and portal vein invasion. A total of 44 HCC cases receiving anatomic liver resection were included in the study and were divided into groups with and without PVI. The prevalence of VM in each group was examined by CD34-PAS dual staining. The regulatory molecules of VM formation such as Notch1, Vimentin and matrix metalloproteinases (MMPs) were investigated by immunohistochemical staining. Analysis was performed to explore the association of PVI, VM and the VM regulatory molecules. PVI was found in 40.91% (18/44) cases and VM was found in 38.64% (17/44) cases in total samples. The incidence of VM was 72.22% (13/18) in PVI group while it was 15.38% (4/26) in non-PVI group (PPVI (r=0.574, PPVI in HCC patients. Taken together, our results suggested that VM formation, alone with its regulatory molecules, is the promoting factor of PVI in hepatocellular carcinoma.

  17. Telomerase-specific oncolytic virotherapy for human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    AIM: To evaluate the therapeutic efficiency of replicative adenovirus CNHK300 targeted in telomerase-positive hepatocellular carcinoma. METHODS: CNHK300, ONYX-015 (55 kDa protein deleted adenovirus) and wtAd5 (wild type adenovirus 5) were compared, and virus proliferation assay, cell viability assay, Western blot and fluorescence microscopy were used to evaluate the proliferation and cytolysis selectivity of CNHK300.RESULTS:The replicative multiples in Hep3B and HepG after 48 h of CNHK300 proliferation were 40625and 65326 fold, respectively, similar to that of wtAd5..However, CNHK300 exhibited attenuated replicative ability in normal fibroblast cell line BJ.CNHK300 could lyse hepatocellular carcinoma cells at a low multiplicity of infection (MOI),but could not affect growth of normal cells even at a high MOI.CONCLUSION:CNHK300 is a cancer-selective replication-competent adenovirus which can cause oncolysis of liver cancer cells as well as wtAd5 (wild type adenovirus 5),but had severely attenuated replicative and cytolytic ability in normal cells. This novel strategy of cancer treatment offers a promising treatment platform.

  18. Evaluating hepatocellular carcinoma cell lines for tumour samples using within-sample relative expression orderings of genes.

    Science.gov (United States)

    Ao, Lu; Guo, You; Song, Xuekun; Guan, Qingzhou; Zheng, Weicheng; Zhang, Jiahui; Huang, Haiyan; Zou, Yi; Guo, Zheng; Wang, Xianlong

    2017-05-08

    Concerns are raised about the representativeness of cell lines for tumours due to the culture environment and misidentification. Liver is a major metastatic destination of many cancers, which might further confuse the origin of hepatocellular carcinoma cell lines. Therefore, it is of crucial importance to understand how well they can represent hepatocellular carcinoma. The HCC-specific gene pairs with highly stable relative expression orderings in more than 99% of hepatocellular carcinoma but with reversed relative expression orderings in at least 99% of one of the six types of cancer, colorectal carcinoma, breast carcinoma, non-small-cell lung cancer, gastric carcinoma, pancreatic carcinoma and ovarian carcinoma, were identified. With the simple majority rule, the HCC-specific relative expression orderings from comparisons with colorectal carcinoma and breast carcinoma could exactly discriminate primary hepatocellular carcinoma samples from both primary colorectal carcinoma and breast carcinoma samples. Especially, they correctly classified more than 90% of liver metastatic samples from colorectal carcinoma and breast carcinoma to their original tumours. Finally, using these HCC-specific relative expression orderings from comparisons with six cancer types, we identified eight of 24 hepatocellular carcinoma cell lines in the Cancer Cell Line Encyclopedia (Huh-7, Huh-1, HepG2, Hep3B, JHH-5, JHH-7, C3A and Alexander cells) that are highly representative of hepatocellular carcinoma. Evaluated with a REOs-based prognostic signature for hepatocellular carcinoma, all these eight cell lines showed the same metastatic properties of the high-risk metastatic hepatocellular carcinoma tissues. Caution should be taken for using hepatocellular carcinoma cell lines. Our results should be helpful to select proper hepatocellular carcinoma cell lines for biological experiments. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. [A single metastasis in the carpal bones as the first clinical manifestation of a hepatocellular carcinoma].

    Science.gov (United States)

    Corrales Pinzón, R; Alonso Sánchez, J M; de la Mano González, S; El Karzazi Tarazona, K

    2014-01-01

    Hepatocellular carcinoma is the most common primary tumor of the liver. Spreading outside the liver usually takes place in advanced stages of the disease, and bone is the third most common site of metastases. We present a case of hepatocellular carcinoma in which the first clinical manifestation was a single metastasis to the carpal bones. The interest of this case lies in the way this hepatocellular carcinoma manifested as well as in the unusual site of the metastasis. Copyright © 2012 SERAM. Published by Elsevier Espana. All rights reserved.

  20. ShRNA-targeted COMMD7 suppresses hepatocellular carcinoma growth.

    Directory of Open Access Journals (Sweden)

    Lu Zheng

    Full Text Available BACKGROUND: COMMD7 is a newly identified gene overexpressed in hepatocellular carcinoma (HCC and associated with tumor invasion and poor prognosis. We aim to examine the biological function of COMMD7 in HCC by shRNA silencing. METHODS: COMMD7 expressions were examined in human HCC cell lines HepG2, Huh7, Hep3B, HLE, HLF, SK-Hep-1 and PLC/PRF/5 cells. Recombinant pGenesil-COMMD7-shRNA was transfected into COMMD7-abundant HepG2 cells to silence COMMD7 expression. The effects of COMMD7 silencing on HepG2 cell proliferation in vitro and xenograft tumor growth in vivo were evaluated. Flow cytometry profiling was used to detect the presence of apoptosis in COMMD7-silenced HepG2 cells and to differentiate cell cycle distribution. Electrophoretic mobility shift assay and luciferase reporter assays to examine the activities of nuclear factor-kappaB (NF-κB signaling pathways in response to tumor necrosis factor (TNF-α in COMMD7-silenced HepG2 cells. RESULTS: COMMD7 expression level was abundance in HepG2 and SK-Hep-1 cells. COMMD7 was aberrantly overexpressed in HepG2 cells, whilst pGenesil-COMMD7-shRNA exhibited a maximal inhibition rate of 75%. COMMD7 silencing significantly reduced HepG2 cell proliferation and colony formation. The knockdown of COMMD7 resulted in an increased apoptosis and cell cycle arrest at S-phase. COMMD7 knockdown also exhibited an antineoplastic effect in vivo, which manifested as tumor xenograft growth retardation. COMMD7 silencing also suppressed the responsiveness of NF-κB signaling pathway to the stimulation with TNF-α in vitro. Moreover, the similar suppressive effects of COMMD7 silence on SK-Hep-1 cells were also observed. CONCLUSIONS: COMMD7 contributes to HCC progression by reducing cell apoptosis and overcoming cell cycle arrest. The proliferative and antiapoptotic effects of COMMD7 may be mediated by NF-κB signaling pathway.

  1. New Natural Pigment Fraction Isolated from Saw Palmetto: Potential for Adjuvant Therapy of Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Hor-Yue Tan

    2016-08-01

    Full Text Available For the first time, we discovered a small proportion of aqueous fraction from Saw Palmetto apart from the fatty acid-rich fraction exhibited pharmacological activity. Therefore, this study aims to explore the anti-tumor potential of red pigmented aqueous fraction of Saw Palmetto, NYG on human hepatocellular carcinoma and its possible targets. Subcutaneous xenograft and orthotopic implantation models of HCC were used to evaluate the tumor inhibitory effect of NYG. Human hepatocellular carcinoma (HCC cell lines and human umbilical vein endothelial cells (HUVEC were used as in vitro model. The mRNA expression was conducted by qPCR. Protein expression was monitored by immunoblotting and immunohistochemistry. Cell migration and blood vessel formation were determined by chamber assay and tube formation assay, respectively. Significant tumor inhibition of NYG in dose-dependent manner was observed on subcutaneous xenograft and orthotopic HCC model. NYG has no direct action on cell viability or VEGF secretion of HCC cells. However, NYG reduced in vitro migration and vessel formation activities of HUVEC cells, as well as in vivo intratumoral neovascularization. NYG attenuated extracellular signal-regulated kinases (ERK activation in endothelial cells, which may be associated with the suppression of migration and tube formation of HUVEC. NYG suppressed tumor expansion of HCC via inhibiting neovascularization, and may be potential adjuvant treatment for HCC.

  2. Nuclear and mitochondrial DNA microsatellite instability in hepatocellular carcinoma in Chinese

    Institute of Scientific and Technical Information of China (English)

    Dian-Chun Fang; Li Fang; Rong-Quan Wang; Shi-Ming Yang

    2004-01-01

    AIM: To study the nuclear microsatellite instability (nMSI)at BAT26 and mitochondral microsalellite instability (mtMSI)in the occurrence and development of hepatocellular carcinoma and the relationship between nMSI and mtMSI.METHODS: nMSI was observed with PCR and mtMSI with PCR-SSCP in 52 cases of hepatocellular carcinoma.RESULTS: mtMSI was detected in 11 out of the 52 cases of hepatocellular carcinoma (21.2%). Among the 11 cases of hepatocellular carcinoma with mtMSI, 7 occured in one locus and 4 in 2 loci. The frequency of mtMSI in the 52 cases of hepatocellular careinoma showed no correlation to sex, age,infection of hepatitis B, liver cirrhosis as well as positive AFP of the patients (P>0.05). In addition, nMSI was detected in 3 out of 52 cases of hepatocellular carcinoma (5.8%) and there was no correlation of the incidence of mtMSI to that CONCLUSION: mtMSI may be involved in the coccurrence and development of hepatocellular carcinoma and it is independent of nMSI.

  3. The evaluation of p,p'-DDT exposure on cell adhesion of hepatocellular carcinoma.

    Science.gov (United States)

    Jin, Xiaoting; Chen, Meilan; Song, Li; Li, Hanqing; Li, Zhuoyu

    2014-08-01

    Many studies have found a positive association between the progression of hepatocellular carcinoma and DDT exposure. These studies mainly focus on the effect of DDT exposure on cell proliferation and epithelial to mesenchymal transition (EMT) promotion. However, the influence of DDT on cell adhesion of hepatocellular carcinoma remains to be unclear. The aim of our study was to determine the effect of p,p'-DDT on cell adhesion of hepatocellular carcinoma in vitro and in vivo. The data showed that p,p'-DDT, exposing HepG2 cells for 6 days, decreased cell-cell adhesion and elevated cell-matrix adhesion. Strikingly, p,p'-DDT increased reactive oxygen species (ROS) content, and this was accompanied by the activation of JAK/STAT3 pathway. Moreover, ROS inhibitor supplement reversed these effects significantly. However, the addition of ER inhibitor, ICI, had no effect on the p,p'-DDT-induced effects. p,p'-DDT altered the mRNA levels of related adhesion molecules, including inhibition of E-cadherin and promotion of N-cadherin along with CD29. Interestingly, the p,p'-DDT-altered adhesion molecules could be reversed with JAK inhibitor or STAT3 inhibitor. Likewise, p,p'-DDT stimulated the JAK/STAT3 pathway in nude mice, as well as altered the mRNA levels of E-cadherin, N-cadherin, and CD29. Taken together, these results indicate that p,p'-DDT profoundly promotes the adhesion process by decreasing cell-cell adhesion and inducing cell-matrix adhesion via the ROS-mediated JAK/STAT3 pathway. All these events account for the carcinogenic potential of p,p'-DDT in liver.

  4. Primary hepatocellular carcinoma in ectopic liver masquerading as left adrenal carcinoma: a rare occurrence

    Directory of Open Access Journals (Sweden)

    Shailendra Kumar

    2010-06-01

    Full Text Available We report a unique case of primary hepatocellular carcinoma in an ectopic liver rest in the left renal hilum masquerading as a left adrenal tumor. Adrenal tumors have been reported within adrenal rests inside the liver but hepatocellular carcinoma in ectopic liver rests in the adrenal area is an extremely rare entity. To the best of our knowledge, this is the first case report from the Indian subcontinent to describe this event in the English literature. Our patient, a sixty-year-old, non-diabetic, non-hypertensive male, presented with a history of left flank pain for the past six months. He was a chronic smoker and also consumed excessive amounts of alcohol. He had chronic obstructive pulmonary disease and was hepatitis B surface antigen positive. A contrast enhanced computer tomography scan of the abdomen showed an 8¥8¥8 cm, well-defined, heterogeneously enhancing mass with central necrosis, in the left suprarenal region. The provisional diagnosis of an adrenal tumor was made and open transperitoneal excision of the tumor along with two enlarged lymph nodes was done. Immunohistochemistry staining of the specimen revealed it to be a primary hepatocellular carcinoma. The patient died within six months of surgery owing to extensive metastases. We concluded that chronic hepatitis B infection and chronic and excessive alcohol consumption and/or chronic smoking may have been the predisposing factors for the occurrence of primary hepatocellular carcinoma in the liver rest in our patient. The prognosis appears to be poor despite surgical management.

  5. High expression of G-protein signaling modulator 2 in hepatocellular carcinoma facilitates tumor growth and metastasis by activating the PI3K/AKT signaling pathway.

    Science.gov (United States)

    He, Xiao-Qin; Zhang, Yue-Feng; Yu, Jia-Jun; Gan, Yuan-Yuan; Han, Na-Na; Zhang, Mei-Xia; Ge, Wei; Deng, Jun-Jian; Zheng, Yong-Fa; Xu, Xi-Ming

    2017-03-01

    The aim of this study was to investigate the role of G-protein signaling modulator 2 in the carcinogenesis and progression of hepatocellular carcinoma. We previously showed that G-protein signaling modulator 2 was upregulated in hepatitis B virus-related hepatocellular carcinoma tissues through a hierarchical clustering analysis. With this study, we first assessed the expression pattern of G-protein signaling modulator 2 in hepatocellular carcinoma specimens and adjacent noncancerous tissues; clinical data were analyzed, along survival times, utilizing the Kaplan-Meier method. Moreover, the functions of G-protein signaling modulator 2 were examined using small-interfering RNAs in vitro. The results showed that G-protein signaling modulator 2 was clearly overexpressed in hepatocellular carcinoma tissues and cell lines and that the G-protein signaling modulator 2 expression level was related to tumor size and hepatitis B virus infection. Furthermore, G-protein signaling modulator 2 knockdown studies suggested that G-protein signaling modulator 2 accelerates cell growth, cell cycle, migration, and invasion and inhibits apoptosis, acting as an oncogene in hepatocellular carcinoma. Western blotting indicated that silencing of G-protein signaling modulator 2 in HepG2 and SMMC-7721 cells increased the expression levels of Bax, caspase-3, and E-cadherin, while notably suppressing the cyclin-dependent kinase 4, cyclin-dependent kinase 6, CyclinD1, Snail1, Vimentin, and matrix metallopeptidase 9 expression levels, compared with that in the control groups. In addition, we found that G-protein signaling modulator 2 can affect the expression of key proteins involved in protein kinase B activation. In conclusion, high expression of G-protein signaling modulator 2 was involved in the pathological processes of hepatocellular carcinoma through activation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, which may provide an attractive potential diagnostic

  6. Cure is Possible with Salvage Surgery following Downstaging of Hepatocellular Carcinoma

    Institute of Scientific and Technical Information of China (English)

    LauW.Y.

    2004-01-01

    Combined modality non-surgical treatment can effectively downstage unresectable hepatocellular carcinoma in some patients to become resectable. Salvage surgery following tumour-downstaging can be curative in these patients.

  7. Combined hepatocellular and cholangiocellular carcinoma presenting with radiological characteristics of focal nodular hyperplasia

    Institute of Scientific and Technical Information of China (English)

    Inneke Willekens; Anne Hoorens; Caroline Geers; Bart Op de Beeck; Frederik Vandenbroucke; Johan de Mey

    2009-01-01

    Combined hepatocellular and cholangiocellular carcinoma (cHCC-CC) is a rare tumor type containing unequivocal elements of both hepatocellular carcinoma and cholangiocarcinoma that are intimately mixed.Although these tumors are usually considered to be more related to hepatocellular carcinoma than to cholangiocarcinoma, they sometimes, in contrast to hepatocellular carcinoma, contain a significant amount of fibrous stroma. This might in some cases explain atypical radiological features. We report a case of a cHCC-CC in a 47-year-old female that resembled focal nodular hyperplasia on Magnetic Resonance Imaging.Correlation of imaging and serum levels of α-fetoprotein and CA19.9 can help to make the correct diagnosis preoperatively.

  8. Hemodynamic study of hepatocellular car-cinoma nodules by multi-slice spiral computed tomographic perfusion

    Institute of Scientific and Technical Information of China (English)

    马国林

    2013-01-01

    Objective To analyze the 64-slice computed tomographic(CT) perfusion parameters of hepatocellular carcinoma(HCC) nodule so as to assess the diagnostic value of hemodynamic changes of HCC nodule by this perfusion

  9. Expression and survival prediction of microRNA-155 in hepatocellular carcinoma after liver transplantation

    Institute of Scientific and Technical Information of China (English)

    韩中博

    2013-01-01

    Objective To explore the expression of microRNA-155in hepatocellular carcinoma(HCC)and its contribution to recurrence and prognosis of HCC after liver transplantation(LT).Methods The expression levels

  10. Expression and survival prediction of microRNA-155 in hepatocellular carcinoma after liver transplantation

    Institute of Scientific and Technical Information of China (English)

    韩中博

    2013-01-01

    Objective To explore the expression of microRNA-155in hepatocellular carcinoma(HCC)and its contribution to recurrence and prognosis of HCC after liver transplantation(LT).Methods The expression levels of

  11. Regulator of Calcineurin 1 Gene Isoform 4, Down-regulated in Hepatocellular Carcinoma, Prevents Proliferation, Migration, and Invasive Activity of Cancer Cells and Metastasis of Orthotopic Tumors by Inhibiting Nuclear Translocation of NFAT1.

    Science.gov (United States)

    Jin, Haojie; Wang, Cun; Jin, Guangzhi; Ruan, Haoyu; Gu, Dishui; Wei, Lin; Wang, Hui; Wang, Ning; Arunachalam, Einthavy; Zhang, Yurong; Deng, Xuan; Yang, Chen; Xiong, Yi; Feng, Hugang; Yao, Ming; Fang, Jingyuan; Gu, Jianren; Cong, Wenming; Qin, Wenxin

    2017-09-01

    Individuals with Down syndrome have a low risk for many solid tumors, prompting the search for tumor suppressor genes on human chromosome 21 (HSA21). We aimed to identify and explore potential mechanisms of tumor suppressors on HSA21 in hepatocellular carcinoma (HCC). We compared expression of HSA21 genes in 14 pairs of primary HCC and adjacent noncancer liver tissues using the Affymetrix HG-U133 Plus 2.0 array (Affymetrix, Santa Clara, CA). HCC tissues and adjacent normal liver tissues were collected from 108 patients at a hospital in China for real-time polymerase chain reaction and immunohistochemical analyses; expression levels of regulator of calcineurin 1 (RCAN1) isoform 4 (RCAN1.4) were associated with clinical features. We overexpressed RCAN1.4 from lentiviral vectors in MHCC97H and HCCLM3 cells and knocked expression down using small interfering RNAs in SMMC7721 and Huh7 cells. Cells were analyzed in proliferation, migration, and invasion assays. HCC cells that overexpressed RCAN1.4 or with RCAN1.4 knockdown were injected into livers or tail veins of nude mice; tumor growth and numbers of lung metastases were quantified. We performed bisulfite pyrosequencing and methylation-specific polymerase chain reaction analyses to analyze CpG island methylation. We measured phosphatase activity of calcineurin in HCC cells. RCAN1.4 mRNA and protein levels were significantly decreased in primary HCC compared with adjacent noncancer liver tissues. Reduced levels of RCAN1.4 mRNA were significantly associated with advanced tumor stages, poor differentiation, larger tumor size, and vascular invasion. Kaplan-Meier survival analysis showed that patients with HCCs with lower levels of RCAN1.4 mRNA had shorter time of overall survival and time to recurrence than patients whose tumors had high levels of RCAN1.4 mRNA. In HCC cell lines, expression of RCAN1.4 significantly reduced proliferation, migration, and invasive activity. HCC cells that overexpressed RCAN1.4 formed smaller

  12. Nonlinear tumor evolution from dysplastic nodules to hepatocellular carcinoma.

    Science.gov (United States)

    Joung, Je-Gun; Ha, Sang Yun; Bae, Joon Seol; Nam, Jae-Yong; Gwak, Geum-Youn; Lee, Hae-Ock; Son, Dae-Soon; Park, Cheol-Keun; Park, Woong-Yang

    2017-01-10

    Dysplastic nodules are premalignant neoplastic nodules found in explanted livers with cirrhosis. Genetic signatures of premalignant dysplastic nodules (DNs) with concurrent hepatocellular carcinoma (HCC) may provide an insight in the molecular evolution of hepatocellular carcinogenesis. We analyzed four patients with multifocal nodular lesions and cirrhotic background by whole-exome sequencing (WES). The genomic profiles of somatic single nucleotide variations (SNV) and copy number variations (CNV) in DNs were compared to those of HCCs. The number and variant allele frequency of somatic SNVs of DNs and HCCs in each patient was identical along the progression of pathological grade. The somatic SNVs in DNs showed little conservation in HCC. Additionally, CNVs showed no conservation. Phylogenetic analysis based on SNVs and copy number profiles indicated a nonlinear segregation pattern, implying independent development of DNs and HCC in each patient. Thus, somatic mutations in DNs may be developed separately from other malignant nodules in the same liver, suggesting a nonlinear model for hepatocarcinogenesis from DNs to HCC.

  13. A case of spontaneous regression of hepatocellular carcinoma after ultrasound guided liver biopsy

    Energy Technology Data Exchange (ETDEWEB)

    Jo, Jeong Hyun [Dept. of Radiology, Dong A University Hospital, Dong A University College of Medicine, Busan (Korea, Republic of)

    2014-10-15

    Spontaneous regression of hepatocellular carcinoma after liver biopsy has not been reported in the English literature. Herein, we present a case of partial spontaneous regression of hepatocellular carcinoma after ultrasound guided liver biopsy in a 64-year-old female. During 28 months, the tumor, which had been shrinking, showed no interval change. However, after 28 months, tumor showed regrowth, which led to a segmentectomy.

  14. Interaction of DNA repair gene polymorphisms and aflatoxin B1 in the risk of hepatocellular carcinoma

    OpenAIRE

    2014-01-01

    Aflatoxin B1 (AFB1) is an important environmental carcinogen and can induce DNA damage and involve in the carcinogenesis of hepatocellular carcinoma (HCC). The deficiency of DNA repair capacity related to the polymorphisms of DNA repair genes might play a central role in the process of HCC tumorigenesis. However, the interaction of DNA repair gene polymorphisms and AFB1 in the risk of hepatocellular carcinoma has not been elucidated. In this study, we investigated whether six polymorphisms (i...

  15. Clinical Characteristics of Patients with Hepatocellular Carcinoma in a Middle Eastern Population

    OpenAIRE

    Alswat, Khalid A; Sanai, Faisal M.; Altuwaijri, Mansour; Albenmousa, Ali; Almadi, Majid; Al-Hamoudi, Waleed K.; Abdo, Ayman A.

    2013-01-01

    Background Hepatocellular carcinoma (HCC) is one of the leading causes of death in Saudi male patients. Local clinical and demographic data of this disease are scarce. Objectives We sought to describe the clinical characteristics and outcomes of patients from two tertiary care centers in Saudi Arabia. Patients and Methods Data were collected for all patients diagnosed to have hepatocellular carcinoma between June 2003 and July 2008 who had been registered in a special research database (the S...

  16. Dermatomyositis associated with hepatitis B virus-related hepatocellular carcinoma.

    Science.gov (United States)

    Yang, Suh Yoon; Cha, Bong Ki; Kim, Gihyeon; Lee, Hyun Woong; Kim, Jae Gyu; Chang, Sae Kyung; Kim, Hyung Joon

    2014-03-01

    Dermatomyositis is an idiopathic inflammatory myopathy with typical cutaneous manifestations. It has been proposed that dermatomyositis may be caused by autoimmune responses to viral infections. Previous studies have shown an association between dermatomyositis and malignant tumors such as ovarian cancer, lung cancer, and colorectal cancer. However, a chronic hepatitis B virus (HBV) infection associated with dermatomyositis and hepatocellular carcinoma (HCC) has been very rarely reported. Here, we report a rare case of dermatomyositis coinciding with HBV-associated HCC. A 55-year-old male was confirmed to have HCC and dermatomyositis based on proximal muscle weakness, typical skin manifestations, elevated muscle enzyme levels, and muscle biopsy findings. This case suggests that HCC and/or a chronic HBV infection may be factors in the pathogenesis of dermatomyositis through a paraneoplastic mechanism.

  17. Radiotherapy for multiple brain metastases from hepatocellular carcinomas

    Institute of Scientific and Technical Information of China (English)

    Nobuyuki Toshikuni; Kazuhiko Morii; Michinori Yamamoto

    2007-01-01

    A 78-year-old man with liver cirrhosis was found to have multiple hepatocellular carcinomas (HCCs)and underwent 3 sessions of transcatheter arterial chemoembolization. Fourteen months after diagnosis,the patient presented with left hemiparesis. Contrastenhanced magnetic resonance imaging showed multiple metastases with ring-shaped enhancement in the cerebrum and cerebellum. There were no metastases to other organs. The metastatic lesions almost completely disappeared after whole-brain radiotherapy with a total dose of 50 Gy. Neurologic symptoms decreased,and the patient's quality of life improved. The patient underwent 2 more sessions of transcatheter arterial chemoembolization. Twelve months after the diagnosis of brain metastasis, the patient remains alive. The present case indicates that radiotherapy can improve quality of life and prolong survival in some patients with brain metastases from HCCs.

  18. Update on new approaches in the management of hepatocellular carcinoma.

    Science.gov (United States)

    Cabibbo, Giuseppe; Antonucci, Michela; Genco, Chiara

    2010-11-26

    Hepatocellular carcinoma (HCC) is a major health problem. It is currently the third cause of cancer-related death, it is highly prevalent in the Asia-Pacific region and Africa, and is increasing in Western countries. The natural history of HCC is very heterogeneous and prediction of survival in individual patients is not satisfactory because of the wide spectrum of the disease. During the past decade, major advances have been achieved in prevention, through better surveillance of patients at risk, and in therapy through better surgical and ablative therapies and multimodal treatment approaches. Moreover, the increasing knowledge of molecular hepatocarcinogenesis provides the opportunity for targeted therapies. In this setting, the impact of sorafenib on advanced-stage HCC is a landmark finding in the treatment of liver cancer. The role of sorafenib administration as adjuvant therapy after curative treatment is being evaluated in clinical studies. Future research should lead to a molecular classification of the disease and a more personalized treatment approach.

  19. Epigenetic Regulation in Hepatocellular Carcinoma Requires Long Noncoding RNAs

    Directory of Open Access Journals (Sweden)

    Laura Amicone

    2015-01-01

    Full Text Available Recent evidence has proven the relevance of epigenetic changes in the development of hepatocellular carcinoma (HCC, the major adult liver malignancy. Moreover, HCC onset and progression correlate with the deregulation of several long noncoding RNAs (lncRNAs, exhibiting great biological significance. As discussed in this review, many of these transcripts are able to specifically act as tumor suppressors or oncogenes by means of their role as molecular platforms. Indeed, these lncRNAs are able to bind and recruit epigenetic modifiers on specific genomic loci, ultimately resulting in regulation of the gene expression relevant in cancer development. The evidence presented in this review highlights that lncRNAs-mediated epigenetic regulation should be taken into account for potential targeted therapeutic approaches.

  20. Hepatocellular Carcinoma in Patients with Chronic Hepatitis C

    Directory of Open Access Journals (Sweden)

    Dmitry Konstantinov

    2016-09-01

    Full Text Available The purpose of the study was to examine the clinical and epidemiological data in patients with chronic hepatitis C (CHC and hepatocellular carcinoma (HCC before they sought specialized medical care. The study included 92 patients with CHC. All patients were divided into 2 groups: Group 1 consisted of CHC patients with HCC (n=45, and Group 2 (n=47 consisted of CHC patients without HCC. With the development of HCC in CHC patients, clinical manifestations were absent only in 2.2% of patients. Determining factors in HCC development are male sex, mature age, the maintained HCV replication, moderate and severe fibrosis, disease duration of more than 10 years, and the lack of effect of antiviral treatment.

  1. Research advances in cellular immunotherapy for primary hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    ZHANG Ye

    2014-09-01

    Full Text Available The present therapy for primary hepatocellular carcinoma (HCC consists of surgery as well as local radiotherapy and chemotherapy. However, the majority of patients are susceptible to recurrence after comprehensive treatment, and the overall treatment outcome is not ideal due to the lack of effective drugs and strategies. Increasing evidence has demonstrated that the immune system is closely related to the development, progression, metastasis, and recurrence of HCC. Thus, immune therapy, especially cellular immunotherapy, could regulate immune function and induce specific antitumor immunity to achieve the goal of controlling HCC and reducing its recurrence and metastasis, which has become an essential part in the comprehensive treatment of HCC. The findings in preclinical and clinical studies on cellular immunotherapy for HCC data are reviewed, and the current problems are discussed.

  2. Regression of hepatocellular carcinoma during vitamin K administration

    Institute of Scientific and Technical Information of China (English)

    Kazuhiro Nouso; Nobuaki Okano; Masahiro Nakagawa; Motowo Mizuno; Yasuyuki Araki; Yasushi Shiratori; Shuji Uematsu; Kunihiro Shiraga; Ryoichi Okamoto; Ryo Harada; Shoko Takayama; Wakako Kawai; Shigeru Kimura; Toru Ueki

    2005-01-01

    An 85-year-old man with HCV infection and diabetes mellitus was diagnosed as having hepatocellular carcinoma (HCC, 13 cm in diameter) based on high serum alpha-fetoprotein (AFP),AFP-L3,and des-γ-carboxy prothrombin levels as well as typical enhancement pattern on contrast-enhanced CT. The patient did not receive any interventional treatments because of advanced age and the advanced stage of HCC.He chose to take vitamin K,which was reported to suppress the growth of HCC in vitro. Three months after starting vitamin K, all three tumor markers were normalized and HCC was markedly regressed, showing no enhancement in the early arterial phase on CT. Here we present the report describing the regression of HCC during the administration of vitamin K.

  3. Metastatic hepatocellular carcinoma of the external auditory canal

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    This report describes a rare case of metastatic hepatocellular carcinoma (HCC) presenting a huge mass in the left external auditory canal (EAC). The patient was a 55-year-old man with hepatitis B virus-related HCC.He presented to our department with a three-month history of increasing left otalgia, and hearing loss with recent fresh aural bleeding. Histopathologic examination indicated that the tumor was secondary to HCC. Although external irradiation was not effective, the tumor was treated with surgical debulking and high dose rate 192 Ir remote afterloading system (RALS) for postoperative intracavitary irradiation. A review of the literature revealed only five other cases of HCC metastasis to the temporal bone, all of which mainly metastasteed in the internal acoustic meatus. The present case is the first report of HCC metastasis to the EAC.

  4. Towards the optimization of management of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Xi Feng; Madhava Pai; Malkhaz Mizandari; Tinatin Chikovani; Duncan Spalding; Long Jiao; Nagy Habib

    2011-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common neoplasm in the world,closely correlated with viral hepatitis and liver cirrhosis.The vast majority of HCC patients present at a late stage and are unsuitable for surgery due to limited liver functional reserve.Tumors can involve major vessels or hilar structures,necessitating major liver resection and/or rendering liver resection unfeasible.A series of new technologies have been developed to optimise HCC management.Stem cell therapy improves impaired liver functional reserve prior to liver resection,Intravascular radiofrequency ablation recanalises the portal vein invaded by tumour thrombus and endobiliary radiofrequency ablation restores and extends biliary patency of the bile duct invaded by malignancy.Laparoscopic radiofrequency assisted liver resection minimizes blood loss and avoids liver warm ischemia,while increasing parenchymal sparing.These benefits combined maximize the safety of liver resection.

  5. Small Bowel Metastasis of Hepatocellular Carcinoma Detected by Capsule Endoscopy

    Directory of Open Access Journals (Sweden)

    A. Igawa

    2013-11-01

    Full Text Available We report a rare case of metastasis of hepatocellular carcinoma (HCC to the small bowel that presented as a pedunculated epithelial polyp. A 60-year-old man with liver cirrhosis type B was treated for HCC (stage IVb at our hospital. He had been admitted for melena and anemia. Capsule endoscopy was performed in this patient with obscure gastrointestinal bleeding. It showed a polypoid lesion with bleeding in the ileum. Double-balloon endoscopy was performed. The lesion was determined to be a pedunculated polyp in the ileum. Histological examination of biopsy specimens showed tumor cells resembling HCC. We performed endoscopic mucosal resection for the lesion by double-balloon endoscopy to prevent bleeding from the tumor. The patient had no melena or anemia and his condition improved after endoscopic mucosal resection. However, he died of liver failure 2 months later.

  6. Next big threat for Pakistan Hepatocellular Carcinoma (HCC).

    Science.gov (United States)

    Parkash, Om; Hamid, Saeed

    2016-06-01

    In our country, world hepatitis day (28th May 2013) was observed as a liver cancer day to draw global attention on the global health menace caused by Hepatocellular carcinoma (HCC). This is the right time to write a review article to apprise the nation of this growing burden of HCC caused most commonly by viruses in our country. Pakistan is also recognized as one of the countries of the world where hepatitis C virus (HCV) is endemic. Recent large national surveys suggest an overall HCV prevalence of 4.8% and that of HBV as 2.5%. There are however communities where the sero-prevalence of HCV can be as high as 23%. No wonder that chronic liver disease is the fifth most common reason for morbidity and mortality in the country and Pakistan has been perhaps accurately called a "cirrhotic state". Hence majority of such patients are at risk of developing HCC.

  7. Management before hepatectomy for hepatocellular carcinoma with cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Hisashi; Nakayama; Tadatoshi; Takayama

    2015-01-01

    The global distribution of hepatocellular carcinoma(HCC) varies markedly among regions, and patients in East Asia and Central Africa account for about 80% of all cases. The risk factors are hepatitis B, hepatitis C, alcohol, and etc. The risk of carcinogenesis further increases with progression to hepatic cirrhosis in all liver disorders. Radical treatment of HCC by liver resection without causing liver failure has been established as a safe approach through selection of an appropriate range of resection of the damaged liver. This background indicates that both evaluation of hepatic functional reserve and measures against concomitant diseases such as thrombocytopenia accompanying portal hypertension, prevention of rupture of esophageal varices, reliable control of ascites, and improvement of hypoalbuminemia are important issues in liver resection in patients with hepatic cirrhosis. We review the latest information on perioperative management of liver resection in HCC patients with hepatic cirrhosis.

  8. Hepatogastric Fistula following Transcatheter Arterial Chemoembolization of Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Inderpreet Grover

    2014-10-01

    Full Text Available Hepatogastric fistula (HGF formation following transcatheter arterial chemoembolization (TACE leads to increased morbidity and mortality. A 51-year-old Caucasian male with chronic hepatitis B virus-associated cirrhosis and unresectable hepatocellular carcinoma (HCC presented to the Interventional Radiology Unit for TACE to achieve tumor necrosis. Following the procedure, the patient was admitted with symptoms of fever, epigastric and right upper quadrant pain secondary to the development of an abscess. The abscess was drained; however, an exceedingly rare HGF resulted that was favored to represent a direct invasion of HCC. HGF, the rare complication following TACE, leads to grave consequences and vigilant monitoring, for the development of this entity is recommended to reduce patient mortality. We present a case and literature review of HGF development following TACE for HCC.

  9. Malignant fibrous histiocytoma presenting as hemoperitoneum mimicking hepatocellular carcinoma rupture

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Malignant fibrous histiocytoma (MFH) is a pleomorphic mesenchynal sarcoma. It is uncommonly arises primarily from the intra-peritoneal cavity. Primary peritoneal MFH with tumor bleeding and rupture is rare. We describe the imaging features of a 70-year-old patient presenting with ruptured hemorrhagic peritoneal MFH at subhepatic area, accompanied by massive hemoperitoneum,mimicking a ruptured pedunculated hepatocellular carcinoma. Computed tomography (CT) revealed a large heterogeneous enhanced subhepatic mass with adjacent liver, gallbladder and colon invasion. Tumor hemorrhage and rupture complicated with peritoneal seeding and massive bloody ascites were also detected.Angiography showed a hypervascular tumor fed by enlarged right hepatic arteries, cystic artery and omental branches of gastroepiploic artery. The patient underwent laparotomy for tumor resection, but the tumor recurred one month after operation. To our knowledge, the CT appearance of ruptured intraperitoneal MFH complicated by hemoperitoneum has not been previously described.

  10. Surgical Intervention for Hepatocellular Carcinoma with Bile Buct Thrombi

    Institute of Scientific and Technical Information of China (English)

    PENGShuyou; LIUYingbin; WANGJianwei; CAIXiujun; MOUYiping; WUYulian; FangHeqing; LIJiangtao; WANGXinbao; XUBin; LIHaijun

    2003-01-01

    Objective: To summarize the experience of surgical intervention for hepatocellular carcinoma(HCC) with bile duct thrombi (BDT), and to evaluate the influence on prognosis. Methods: From 1994 to 2002, 15 patients with HCC and BDT who underwent surgical intervention were retrospectively analyzed.Results: The operative procedures included hepatectomy with removel of BDT (n=7), hepatectomy com-bined with extrahepatic bile duct resection (n=4), thrombectomy through choledochotomy (n=3), piggy back orthotopic liver transplantation (n=1). The 1-and 3-year survival rates were 73.3% and 40%, respec-tively. Two patients survived over 5 years. Conclusion: Surgical intervention was effective for patients with HCC and BDT. Operation for recurrent lesion can prolong survival period. Liver transplantation is a new treatment worthy of further investigation.

  11. Imaging of hepatocellular carcinoma; Bildgebung des hepatozellulaeren Karzinoms

    Energy Technology Data Exchange (ETDEWEB)

    Lincke, Therese; Zech, Christoph [Universitaetsspital Basel (Switzerland). Klinik fuer Radiologie und Nuklearmedizin; Boll, Daniel

    2016-12-15

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Besides the improvement in diagnostics and therapy the quantity of new cases and fatalities per year are equal. The main risk factors for HCC developing are liver cirrhosis (causing 90% of HCCs), non-alcoholic fatty liver disease and chronic hepatitis B infection. Therefore, it is recommended to perform an ultrasound screening on patients at risk every 6 month to detect HCC-lesions early. HCC can be definitely diagnosed by imaging techniques using contrast agent such as contrast-enhanced-ultrasound (CEUS), contrast-enhanced-MRI (CE-MRI) and contrast-enhanced-CT (CE-CT). MRI has several advantages compared to the other modalities due to the multi-parametric approach and a higher sensitivity for tumor detection.

  12. [Pathological features of hepatocellular carcinoma carrying hepatitis C virus antigen].

    Science.gov (United States)

    Liu, B; Zhu, S; Zhang, X

    1997-10-01

    To analyze the pathological features of hepatocellular carcinomas (HCCs) carrying different hepatitis virus antigens histopathologically and systematically. PAP and ABC kits were used in the immunohistochemical study, and CAS-200 System was applied in the image cytometry. As compared with HCCs carrying HBV marker(s), the HCCs carrying HCV marker showed more cases of clear cell type (7/9 vs 4/33), better differentiation of cancers, less necrosis of hepatocytes, milder lymphocyte infiltration in the hepatic sinuses or periportal areas (P < 0.01), higher incidence of bile ductule damages, and bore a close relation to the formation of lymphoid follicle in the surrounding tissues (P < 0.05). These patients were elder, with lower grade of symptoms and better prognosis after operation. HCCs carrying only HCAg have different pathological features and clinical characteristics from which carrying HBV marker(s). The results of image cytometry are in accordance with the biological behaviour of HCC.

  13. Proteomics for the early diagnosis and treatment of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Autor OJS

    2007-02-01

    Full Text Available

    The incidence of primary cancer has been increasing globally and now-a-days it constitutes the 5th most frequent cancer of humans representing around 5% of all cancers worldwide. Chronic HBV infection assumes greater significance because of its reported association with cirrhosis, and more ominously hepatocellular carcinoma or HCC. Hepatitis B infection constitutes a major global problem with nearly 400 million infected individuals. It contributes to a significant degree of morbidity on account of the associated chronicity that develops in 5-10% of infected adults and more than 90% of infected neonates. Globally, around one million people suffering from HBVrelated chronic heptatitis and HCC die per year. Despite the availability of an effective prophylactic vaccine against hepatitis B for over 20 years, effective treatment of the chronic disease and associated HCC remains elusive. Therefore, identification of the cellular mediators and effectors of HCC is an important medical objective for developing new diagnostic tools and therapeutic strategies against it. Molecular biomarkers hold great promise for refining our ability to establish early diagnosis and prognosis for HCC, and to predict response to therapy. Proteomics is a rapidly expanding discipline that is expected to change the way in which disease can be diagnosed, treated and monitored in the near future. The proteomic analysis of serum and tumors should allow accurate prediction of what is happening at the protein level in a cancer cell or a body fluid proteome. It is the hope that, by deciphering the alterations in serum and liver proteome, biomarkers and patterns of biomarkers will be found that should be helpful in improving early detection, diagnosis and treatment monitoring of HCC. In the last few years, HCC has been extensively investigated using different proteomic approaches on HCC cell lines

  14. Autoantibodies against tumor-associated antigens fordetection of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the mostcommon tumors worldwide. The survival rate after theonset of symptoms is generally less than one year forthe late presentation of HCC, and reliable tools for earlydiagnosis are lacking. Therefore, novel biomarkers forthe early detection of HCC are urgently required. Recentstudies show that the abnormal release of proteins bytumor cells can elicit humoral immune responses toself-antigens called tumor-associated antigens (TAAs).The corresponding autoantibodies can be detectedbefore the clinical diagnosis of cancer. Therefore, thereis growing interest in using serum autoantibodies ascancer biomarkers. In this review, we focus on theadvances in research on autoantibodies against TAAs asserum biomarker for detection of HCC, the mechanismof the production of TAAs, and the association ofautoantibodies with patients' clinical characteristics.

  15. Vitamin D and K signaling pathways in hepatocellular carcinoma.

    Science.gov (United States)

    Louka, Manal L; Fawzy, Ahmed M; Naiem, Abdelrahman M; Elseknedy, Mustafa F; Abdelhalim, Ahmed E; Abdelghany, Mohamed A

    2017-09-20

    Hepatocellular carcinoma (HCC) is a primary liver malignancy, and is now the six most common in between malignancies. Early diagnosis of HCC with prompt treatment increases the opportunity of patients to survive. With the advances in understanding the molecular biology of HCC, new therapeutic strategies to treat HCC have emerged. There is a growing consensus that vitamins are important for the control of various cancers. Biochemical evidence clearly indicates that HCC cells are responsive to the inhibitory effect of vitamin D, vitamin D analogues and vitamin K. In this review, we summarize the mechanisms used by vitamin D and K to influence the development of HCC and the latest development of vitamin analogues for potential HCC therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Detection of epigenetic aberrations in the development of hepatocellular carcinoma.

    Science.gov (United States)

    Zhang, Yujing

    2015-01-01

    Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide. Hepatocarcinogenesis is a complex, multistep process. It is now recognized that HCC is a both genetic and epigenetic disease; genetic and epigenetic components cooperate at all stages of hepatocarcinogenesis. Epigenetic changes involve aberrant DNA methylation, posttranslational histone modifications and aberrant expression of microRNAs all of which can affect the expression of oncogenes, tumor suppressor genes and other tumor-related genes and alter the pathways in cancer development. Several risk factors for HCC, including hepatitis B and C virus infections and exposure to the chemical carcinogen aflatoxin B1 have been found to influence epigenetic changes. Their interactions could play an important role in the initiation and progression of HCC. Discovery and detection of biomarkers for epigenetic changes is a promising area for early diagnosis and risk prediction of HCC.

  17. Interplay of genetic and epigenetic alterations in hepatocellular carcinoma.

    Science.gov (United States)

    Lee, Sun-Min; Kim-Ha, Jeongsil; Choi, Won-Young; Lee, Jungwoo; Kim, Dawon; Lee, Jinyoung; Choi, Eunji; Kim, Young-Joon

    2016-07-01

    Genetic and epigenetic alterations play prominent roles in hepatocarcinogenesis and their appearance varies depending on etiological factors, race and tumor progression. Intriguingly, distinct patterns of these genetic and epigenetic mutations are coupled not only to affect each other, but to trigger different types of tumorigenesis. The patterns and frequencies of somatic variations vary depending on the nature of the surrounding chromatin. On the other hand, epigenetic alterations often induce genomic instability prone to mutation. Therefore, genetic mutations and epigenetic alterations in hepatocellular carcinoma appear to be inseparable factors that accelerate tumorigenesis synergistically. We have summarized recent findings on genetic and epigenetic modifications, their influences on each other's alterations and putative roles in liver tumorigenesis.

  18. Improving outcomes for patients receiving transarterial chemoembolization for hepatocellular carcinoma.

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    McCurdy, Heather M

    2013-01-01

    Hepatocellular carcinoma is a cancer with increasing incidence in the veteran population. This type of cancer can be treated with transarterial chemoembolization, an invasive procedure performed by specially trained interventional radiologists. The most common serious complications are liver failure, sepsis secondary to ischemic cholecystitis or liver abscess, gastrointestinal bleeding, and death. However, nursing staff and physicians often have little or no experience in caring for patients in the hospital who have had this procedure. Patient safety can be threatened by this lack of knowledge. Sources of threat to patient safety are described by the Institute of Medicine as falling into 4 categories: management, workforce, work processes, and organizational culture. To promote patient safety, defenses need to be deployed to address each category. In this article, the author provides a case example, describes threats to the patient's safety, and describes a plan to improve the care of all patients undergoing this procedure.

  19. Radioembolization for hepatocellular carcinoma using TheraSphere®

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    Safiyya Mohamed Ali

    2011-01-01

    Full Text Available Background/Aim: Hepatocellular carcinoma (HCC is the most common primary malignancy of the liver. Radioembolization with yttrium-90 (Y90 microspheres is a new concept in radiation therapy for HCC. This review focuses on the indications, efficacy, side effects, and future direction of Y90 therapy, using TheraSphere® , in HCC patients. Results: Comprehensive literature reviews have described the clinical and scientific evidence of Y90 therapy. The Radioembolization Brachytherapy Oncology Consortium has concluded that there is sufficient evidence to support the safe and effective use of this locoregional therapy in HCC patients, including those with portal vein thrombosis. Conclusions: There are currently no randomized clinical trials done on TheraSphere® and none of the studies so far have shown a survival benefit. Thus, although it represents a very promising therapy with excellent initial results, it cannot be fully recommended yet, till well-designed, large, randomized clinical studies are conducted showing survival benefits.

  20. Clear cell hepatocellular carcinoma: Back to the basics for diagnosis

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    Puja Sakhuja

    2015-01-01

    Full Text Available Hepatocellular carcinoma (HCC is a common cancer world-wide with a higher incidence in Asia. Clear cell variant of HCC (CCHCC has a frequency ranging from 0.4% to 37%. The presence of 90-100% clear cells is rare. In the present case, a 35-year-old female patient presented with fever and a large abdominal mass in the right hypochondrium. Histology of the tumor revealed >95% clear cells and after taking multiple sections from different areas of tumor only few scattered cells with eosinophilic cytoplasm were found. Immunohistochemistry with Hep Par 1, Glypican 3 and polyclonal carcinoembryonic antigen were negative as were all other markers for metastatic clear cell tumors. Histological diagnosis was based on routine H and E sections showing a histological pattern of architecture with thickened trabeculae. We describe a rare case of CCHCC with >95% clear cells and no immunoreactivity in tumor cells in a non-cirrhotic liver.

  1. Prebiotics: A Novel Approach to Treat Hepatocellular Carcinoma

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    Naz Fatima

    2017-01-01

    Full Text Available Hepatocellular carcinoma is one of the fatal malignancies and is considered as the third leading cause of death. Mutations, genetic modifications, dietary aflatoxins, or impairments in the regulation of oncogenic pathways may bring about liver cancer. An effective barrier against hepatotoxins is offered by gut-liver axis as a change in gut permeability and expanded translocation of lipopolysaccharides triggers the activation of Toll-like receptors which stimulate the process of hepatocarcinogenesis. Prebiotics, nondigestible oligosaccharides, have a pivotal role to play when it comes to inducing an antitumor effect. A healthy gut flora balance is imperative to downregulation of inflammatory cytokines and reducing lipopolysaccharides induced endotoxemia, thus inducing the antitumor effect.

  2. Herbal Medicine and Hepatocellular Carcinoma: Applications and Challenges

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    Yan Li

    2011-01-01

    Full Text Available Use of herbal medicine in the treatment of liver cancer has a long tradition. The compounds derived from the herb and herbal composites are of considerable interest among oncologists. In the past, certain herbal compounds and herbal composite formulas have been studied through in vitro and in vivo as an anti-hepatocellular carcinoma (HCC agent, enhancing our knowledge about their biologic functions and targets. However there is a significant distinction between the herbal medicine and the herbal production even though both are the plant-based remedies used in the practice. In this article, for the sake of clarity, the effective herbal compounds and herbal composite formulas against HCC are discussed, with emphasizing the basic conceptions of herbal medicine in order to have a better understanding of the prevention and treatment of HCC by herbal active compounds and herbal composite formulas.

  3. [Occult hepatitis B virus infection and hepatocellular carcinoma].

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    Lee, Jong Joon; Kwon, Oh Sang

    2013-09-01

    Many studies have suggested that occult HBV infection has a substantial clinical relevance to hepatocellular carcinoma (HCC). Occult HBV infection is an important risk factor for the development of cirrhosis and HCC in patients without HBsAg. As a matter of fact, occult HBV infection is one of the most common causes of crytogenic HCC in endemic areas of HBV. However, there still are controversial issues about the association between occult HBV infection and HCC according to the underlying liver disease. In alcoholic cirrhosis, occult HBV infection may exert synergistic effect on the development of HCC. However, there is insufficient evidence to relate occult HBV infection to hepatocarcinogenesis in non-alcoholic fatty liver disease. In cryptogenic HCC, occult HBV infection may play a direct role in the development of HCC. In order to elucidate the assocciation between occult HBV infection and HCC, underlying liver disease must be specified and larger number of cases must be included in future studies.

  4. Strategies to increase the resectability of hepatocellular carcinoma

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    Wong; Hoi; She; Kenneth; SH; Chok

    2015-01-01

    Hepatocellular carcinoma(HCC) is best treated by liver transplantation, but the applicability of transplantation is greatly limited. Tumor resection in partial hepatectomy is hence resorted to. However, in most parts of the world, only 20%-30% of HCCs are resectable. The main reason for such a low resectability is a future liver remnant too small to be sufficient for the patient. To allow more HCC patients to undergo curative hepatectomy, a variety of ways have been developed to increase the resectability of HCC, mainly ways to increase the future liver remnants in patients through hypertrophy. They include portal vein embolization, sequential transarterial chemoembolization and portal vein embolization, staged hepatectomy, two-staged hepatectomy with portal vein ligation, and Associating Liver Partition and Portal Vein Ligation in Staged Hepatectomy. Herein we review, describe and evaluate these different ways, ways that can be life-saving.

  5. Functional Roles and Therapeutic Applications of Exosomes in Hepatocellular Carcinoma

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    Laura Santangelo

    2017-01-01

    Full Text Available Exosomes are important in intercellular communication. They assure the horizontal transfer of specific functional contents (i.e., proteins, lipids, RNA molecules, and circulating DNA from donor to recipient cells. Notably, tumor-derived exosomes (TDEs appear to be an important vehicle of specific signals in cancer, impacting on tumor growth and metastasis. Recent researches point to the characterization of exosomes in Hepatocellular Carcinoma (HCC, the major adult liver malignancy. In this review, we summarize current findings on HCC exosomes, focusing on the identification of noncoding RNAs as exosome-enriched functional regulators and new potential biomarkers. The great potential of exosomes in future HCC diagnostic and therapeutic approaches is underlined.

  6. MRI Features of Hepatocellular Carcinoma Related to Biologic Behavior

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    Cho, Eun-Suk [Department of Radiology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 135-720 (Korea, Republic of); Choi, Jin-Young [Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of)

    2015-11-01

    Imaging studies including magnetic resonance imaging (MRI) play a crucial role in the diagnosis and staging of hepatocellular carcinoma (HCC). Several recent studies reveal a large number of MRI features related to the prognosis of HCC. In this review, we discuss various MRI features of HCC and their implications for the diagnosis and prognosis as imaging biomarkers. As a whole, the favorable MRI findings of HCC are small size, encapsulation, intralesional fat, high apparent diffusion coefficient (ADC) value, and smooth margins or hyperintensity on the hepatobiliary phase of gadoxetic acid-enhanced MRI. Unfavorable findings include large size, multifocality, low ADC value, non-smooth margins or hypointensity on hepatobiliary phase images. MRI findings are potential imaging biomarkers in patients with HCC.

  7. Hepatocellular carcinoma in elderly patients: challenges and solutions

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    Brunot A

    2016-06-01

    Full Text Available Angélique Brunot, Samuel Le Sourd, Marc Pracht, Julien Edeline Department of Medical Oncology, Centre Eugene Marquis, Rennes, FranceAbstract: Hepatocellular carcinoma (HCC is the second most common cause of death by cancer in the world. Due to the delayed HCC development in hepatitis C carriers and nonalcoholic fatty liver disease, the incidence of HCC in the elderly is increasing and is becoming a global health issue. Elderly patients with HCC should be assessed through proper oncologic approach, namely, screening tools for frailty (Geriatric-8 or Vulnerable Elders Survey-13 and comprehensive geriatric assessment. This review of the literature supports the same treatment options for elderly patients as for younger patients, in elderly patients selected as fit following proper oncogeriatric assessment. Unfit patients should be managed through a multidisciplinary team involving both oncological and geriatrician professionals. Specific studies and recommendations for HCC in the elderly should be encouraged.Keywords: liver cancer, treatment, surgery, geriatric evaluation, sorafenib

  8. Worse or better?-Cirrhosis with hepatocellular carcinoma.

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    Xue, Ran; Meng, Qinghua; Li, Juan; Feng, Jiliang; Shi, Hanping

    2016-12-01

    Hepatocellular carcinoma (HCC) accounts for about 90% of all malignant tumors of liver, ranking fifth in the worldwide incidence of malignant tumors and the third in fatality. More and more evidences suggest that cancer is a metabolic-related disease. From the analysis of recent clinical research data, we found that as the severity of the cirrhosis aggravated, patients with HCC and end-stage liver cirrhosis had a flat energy metabolism which was better than it in patients with simple end-stage liver cirrhosis. Based on these clinical phenomenon, the major aim of this study is to present a new hypothesis: "compensated liver function mechanism" for patients with HCC and liver cirrhosis, cancer cells may play a role to compensate liver function. In this study, we elaborated relevant content about this novel standpoint combined with tumor energy metabolism reprogramming mechanism and tumor cell origin as well as cell exchange mechanism.

  9. Hepatoepigenetic Alterations in Viral and Nonviral-Induced Hepatocellular Carcinoma

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    Mankgopo M. Kgatle

    2016-01-01

    Full Text Available Hepatocellular carcinoma (HCC is a major public health concern and one of the leading causes of tumour-related deaths worldwide. Extensive evidence endorses that HCC is a multifactorial disease characterised by hepatic cirrhosis mostly associated with chronic inflammation and hepatitis B/C viral infections. Interaction of viral products with the host cell machinery may lead to increased frequency of genetic and epigenetic aberrations that cause harmful alterations in gene transcription. This may provide a progressive selective advantage for neoplastic transformation of hepatocytes associated with phenotypic heterogeneity of intratumour HCC cells, thus posing even more challenges in HCC treatment development. Epigenetic aberrations involving DNA methylation, histone modifications, and noncoding miRNA dysregulation have been shown to be intimately linked with and play a critical role in tumour initiation, progression, and metastases. The current review focuses on the aberrant hepatoepigenetics events that play important roles in hepatocarcinogenesis and their utilities in the development of HCC therapy.

  10. Rapid progression of hepatocellular carcinoma after Radiofrequency Ablation

    Institute of Scientific and Technical Information of China (English)

    Andrea Ruzzenente; Giovanni de Manzoni; Matteo Molfetta; Silvia Pachera; Bruno Genco; Matteo Donataccio; Alfredo Guglielmi

    2004-01-01

    AIM: To report the results of radiofrequency ablation (RFA)of hepatocellular carcinoma (HCC) in cirrhotic patients and to describe the treatment related complications (mainly the rapid intrahepatic neoplastic progression).METHODS: Eighty-seven consecutive cirrhotic patients with 104 HCC (mean diameter 3.9 cm, 1.3 SD) were submitted to RFA between January 1998 and June 2003. In all cases RFA was performed with percutaneous approach under ultrasound guidance using expandable electrode needles.Treatment efficacy (necrosis and recurrence) was estimated with dual phase computed tomography (CT) and alphafetoprotein (AFP) level.RESULTS: Complete necrosis rate after single or multiple treatment was 100%, 87.7% and 57.1% in HCC smaller than 3 cm, between 3 and 5 cm and larger than 5 cm respectively (P=0.02). Seventeen lesions of 88(19.3%)developed local recurrence after complete necrosis during a mean follow up of 19.2 mo. There were no treatment-related deaths in 130 procedures and major complications occurred in 8 patients (6.1%). In 4 patients, although complete local necrosis was achieved, we observed rapid intrahepatic neoplastic progression after treatment. Risk factors for rapid neoplastic progression were high preoperative AFP values and location of the tumor near segmental portal branches.CONCLUSION: RFA is an effective treatment for hepatocellular carcinoma smaller than 5 cm with complete necrosis in more than 80% of lesions. Patients with elevated AFP levels and tumors located near the main portal branch are at risk for rapid neoplastic progression after RFA. Further studies are necessary to evaluate the incidence and pathogenesis of this underestimated complication.

  11. Hepatocellular carcinoma: natural history, current management, and emerging tools

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    Tinkle CL

    2012-07-01

    Full Text Available Christopher L Tinkle, Daphne Haas-KoganDepartment of Radiation Oncology, University of California, San Francisco, CA, USAAbstract: Hepatocellular carcinoma (HCC is the most common primary liver tumor and represents the third-leading cause of cancer-related death in the world. The incidence of HCC continues to increase worldwide, with a unique geographic, age, and sex distribution. The most important risk factor associated with HCC is liver cirrhosis, with the majority of cases caused by chronic infection with hepatitis B (HBV and C (HCV viruses and alcohol abuse, although nonalcoholic fatty liver disease is emerging as an increasingly important cause. Primary prevention in the form of HBV vaccination has led to a significant decrease in HBV-related HCC, and initiation of antiviral therapy appears to reduce the incidence of HCC in patients with chronic HBV or HCV infection. Additionally, the use of ultrasonography enables the early detection of small liver tumors and forms the backbone of recommended surveillance programs for patients at high risk for the development of HCC. Cross-sectional imaging studies, including computed tomography and magnetic resonance imaging, represent further noninvasive techniques that are increasingly employed to diagnose HCC in patients with cirrhosis. The mainstay of potentially curative therapy includes surgery – either resection or liver transplantation. However, most patients are ineligible for surgery, because of either advanced disease or underlying liver dysfunction, and are managed with locoregional and/or systemic therapies. Randomized controlled trials have demonstrated a survival benefit with both local therapies, either ablation or embolization, and systemic therapy in the form of the multikinase inhibitor sorafenib. Despite this, median survival remains poor and recurrence rates significant. Further advances in our understanding of the molecular pathogenesis of HCC hold promise in improving the

  12. Current concepts in pathophysiology and management of hepatocellular carcinoma.

    Science.gov (United States)

    Hamza, Amal H; Abdulfattah, Hanaa M; Mahmoud, Rasha H; Khalil, Wagdy K B; Ahmed, Hanaa H

    2015-01-01

    Additional approaches to control malignancies are needed due to the emerging trends in the incidence of cancer of different organ sites. Due to the high frequency of hepatocellular carcinoma (HCC) and its poor prognosis, preventing HCC is an urgent priority. To explore the antioxidant and apoptotic pathways of grape seed extract (GSE) we induce HCC experimentally by diethylnitrosoamine (DEN) and treated the animals with low and high doses of GSE. The results indicate good therapeutic possibilities for GSE use in treatment of HCC., This was evidenced via regression of liver enzymes' function (ALT&AST), the HCC markers; α-fucosidase, α-fetoprotein and carcinoembrionic antigen (CEA) in HCC groups treated with the grape seed extract. Also, tumor necrosis factor (TNF-α) showed a significant decrease using GSE in HCC bearing animals. Regarding the apoptotic pathways of GSE, we found a significant down regulation of apoptosis enhancing nuclease (Aen), Bcl2-associated X protein (Bax), B-cell translocation gene 2(Btg2), Cyclin G1 (Ccng1) and Cyclin-dependent kinase inhibitor 1A (Cdkn1a) gene expression in HCC+GSE groups as compared to HCC bearing group. In the same trend, the necrotic/apoptotic rates were significantly higher in the HCC groups treated with GSE vs. the HCC bearing group. Finally, the 8-OHdG/2-dG generation decreased by 73.8% and 52.9% in HCC+GSE at low and high doses, respectively. Based on these encouraging observations, grape seed extract could be a promising natural remedy for attenuating hepatocellular carcinoma that has a great future in approaches directed towards control of HCC.

  13. Liver Transplantation and Cirrhotomimetic Hepatocellular Carcinoma: Classification and Outcomes

    Science.gov (United States)

    Clayton, Erica F; Malik, Saloni; Bonnel, Alexander; Mu, Yifei; Olthoff, Kim; Shaked, Abraham; Abt, Peter L; Peterman, Heather; Reddy, K. Rajender; Ottmann, Shane; Furth, Emma E; Levine, Matthew H

    2014-01-01

    Background & Aims Liver transplantation has become the standard of care treatment for hepatocellular carcinoma (HCC) that falls within size and numeric criteria in cirrhotic patients. Cirrhotomimetic (CMM) hepatocellular carcinoma is an uncommon growth pattern that infiltrates cirrhotic parenchyma, can become extensive in size, and can evade detection via radiologic studies. Liver transplant outcomes for this type of HCC is not well reported but generally considered to be poor. We wished to better describe this variant of HCC in explanted livers, derive a classification system for this tumor type, and assess the outcomes of liver transplantation for this tumor variant. Methods Upon retrospective analysis of all patients transplanted at a single center for HCC in 1996–2009 (358 patients) a series of 26 patients exhibiting CMM growth pattern were identified. We developed a classification system for this tumor growth pattern variant and determined patient and tumor-specific outcomes. Results We derived a classification schema of CMM HCC based upon tumor extent and cellular histopathology with clear cell pathology being associated with favorable outcome. We note a 100% 3-year and 58.3% 5-year recurrence free survival after transplant in those with tumor confined to one lobe who have clear cell pathology versus 16.2% 3- and 5-year recurrence free survival in those who do not meet these criteria. Conclusion Cirrhotomimetic HCC features are noted in 7% of patients transplanted for HCC in our center with favorable outcomes inpatients with clear cell histology and growth involving less than 50% of the liver. PMID:24668931

  14. Hepatocellular carcinoma:current management and recent advances

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    Wan-Yee Lau; Eric C. H. Lai

    2008-01-01

    BACKGROUND:Hepatocellular carcinoma (HCC) is a major health problem worldwide. It is the iffth most common cancer in the world, and the third most common cause of cancer-related death. Without speciifc treatment, the prognosis is very poor. The goal of management is"cancer control"-a reduction in its incidence and mortality as well as an improvement in the quality of life of patients with HCC and their families. This article aims to review the current management of HCC and its recent advances. DATA SOURCES:A MEDLINE database search was performed to identify relevant article using the keywords"hepatocellular carcinoma", "hepatectomy", "liver transplantation", and"local ablative therapy". Additional papers and book chapters were identiifed by a manual search of the references from the key articles. RESULTS:Liver resection and liver transplantation remain the options that give the best chance of a cure. Recent evidence suggests that local ablative therapy may offer comparable survival results in patients with small HCC, and preserved liver function. Transarterial chemoembolization (TACE) is the most promising palliative modality for unresectable HCC, but other techniques, such as transarterial radioembolization (TARE), and local ablative therapy, have also shown comparable results. CONCLUSIONS:Early diagnosis of HCC remains a key goal in improving the prognosis of patients. During the last two decades, operative mortality and surgical outcome of liver resection and liver transplantation for HCC have improved. Progress also has been made in multi-modality therapy which can increase the chance of survival and improve the quality of life for patients with advanced HCC.

  15. Mexican consensus on the diagnosis and management of hepatocellular carcinoma.

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    González Huezo, María Sarai; Sánchez Ávila, Juan Francisco

    2014-01-01

    There has been an increase in the incidence of hepatocellular carcinoma (HCC) worldwide and information on this disease is limited in Mexico. To analyze the available evidence on the diagnosis and treatment of HCC in the Mexican population. The Mexican Association of Hepatology organized a meeting that 24 medical specialists interested in HCC attended. An electronic database search was carried out to identify documents published from 2000 with the keywords «Hepatocellular carcinoma» and «Mexico», «epidemiology», «diagnosis», and «treatment». The incidence of HCC in Mexico has increased over the last few decades. The mean age of disease presentation is in patients from 60 to 70 years old, and the man:woman ratio appears to be equal. HCC is frequently associated with underlying hepatopathy and the primary cause reported in our country is chronic hepatitis C virus) infection. Surveillance is recommended for high-risk groups in Child-Pugh stages A and B, and for those in stage C if the patient is on a waiting list or regarded as a candidate for liver transplantation. HCC should be evaluated by a multidisciplinary team of experts in the field. HCC is a neoplasia that is on the rise in Mexico, with epidemiologic characteristics similar to those of other populations. Diagnosis and treatment should be individualized in accordance with these Consensus guidelines. Copyright © 2013 Asociación Mexicana de Gastroenterología. Published by Masson Doyma México S.A. All rights reserved.

  16. Liver transplantation for hepatocellular carcinoma:an update

    Institute of Scientific and Technical Information of China (English)

    Ali Zarrinpar; Fady Kaldas; RonaldW Busuttil

    2011-01-01

    BACKGROUND: Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with multiple etiologies, high incidence, and high mortality. The standard surgical management for patients with HCC consists of locoregional ablation, surgical resection, or liver transplantation, depending on the background state of the liver. Eighty percent of patients initially presenting with HCC are unresectable, either due to the extent of tumor or the level of underlying hepatic dysfunction. While in patients with no evidence of cirrhosis and good hepatic function resection has been the surgical treatment of choice, it is contraindicated in patients with moderate to severe cirrhosis. Liver transplantation is the optimal surgical treatment. DATA  SOURCES: PubMed search of recent articles (from January 2000 to March 2011) was performed looking for relevant articles about hepatocellular carcinoma and its treatment. Additional articles were identified by evaluating references from selected articles. RESULTS: Here we review criteria for transplantation, the types, indications, and role of locoregional therapy in treating the cancer and in downstaging for possible later transplantation. We also summarize the contribution of immunosuppression and adjuvant chemotherapy in the management and prevention of HCC recurrence. Finally we discuss recent advances in imaging, tumor biology, and genomics as we delineate the remaining challenges for the diagnosis and treatment of this disease. CONCLUSIONS: Much can be improved in the diagnosis and treatment of HCC. A great challenge will be to improve patient selection to criteria based on tumor biology. Another will be to incorporate systemic agents post-operatively in patients at high risk for recurrence, paying close attention to efficacy and safety. The future direction of the effort in treating HCC will be to stimulate prospective trials, develop molecular imaging of lymphovascular invasion, to improve recipient selection, and to investigate

  17. Transarterial chemoembolization through collateral vessels in hepatocellular carcinoma

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    Kim, Ji Hye; Han, Joon Koo; Chung, Jin Wook; Park, Jae Hyung; Han, Man Chung [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1993-11-15

    We performed 70 procedures of transarterial chemoembolization (TAE) through extrahepatic collateral vessels (n=27) or parasitic feeders (n=18) in 45 hepatocellular carcinoma patients. The collaterals developed after interruption of the hepatic artery due to repeated TAE (n=17), surgical ligation (n=7)and primary celiac occlusion (n=3). Radiologic findings suggest the existence of parasitic or collateral supply for hepatocellular carcinoma were 1) a focal defect of Lipiodol retention on CT or plain film after TAE via the hepatic artery, 2) dilated and tortuous vessels around the mass on angiography, 3) persistent elevation of the level of serum alpha-fetoprotein or continuous clinical symptoms in spite of sufficient devascularization of the tumor via the hepatic artery, and 4) radiological findings of direct invasion into adjacent organ. The sites of the catheter placement were the inferior phrenic artery(n=19), omental branches(n=16), periportal collaterals (n=6), pancreaticodenal arcade (n=3), gastroduodenal artery(n=3), internal mammary artery (n=2), intercosal artery (n=2), lateral thoracic artery (n=1), bronchial artery (n=1), and colic branches (n=1). Masses feeded by the inferior phrenic and chest wall collaterals were usually located at the dome area of the liver, and the omental and gastroduodenal collaterals developed in the masses located at the inferior tip of the liver. After TAE via collateral vessels, 37 patients underwent follow-up study. In 18 cases(48%), the tumor favorably responded to TAE. Specific complications of collateral TAE were epigastric soreness (n=10), severe shoulder pain (n=4), and embolization of the spinal artery during embolization through the intercostal artery (n=1). In conclusion, various extrahepatic collateals are important alternative or addition routes for effective chemoembolization in patients with advanced hepatoma, and early recognition of the parasitic supply and the effort to perform TAE via collaterals is very

  18. Emerging role of dual antiplatelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma.

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    Aiolfi, Roberto; Sitia, Giovanni

    2014-01-01

    Platelets, the chief effectors of vascular homeostasis, have been identified as important players in the pathogenesis of both acute and chronic liver disease in preclinical models of hepatitis B viral infection. Platelets are thought to promote the accumulation of virus-specific T-cells into the liver parenchyma. Importantly, the inhibition of platelet activation by clinically relevant doses of aspirin and clopidogrel was able to reduce immune-mediated necroinflammatory liver disease, extracellular matrix deposition, and hepatocellular carcinoma development; the same treatment was able to improve overall survival. These results strongly support the design of clinical trials aiming to define the potential of antiplatelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma.

  19. Construction and high cytoplasmic expression of a tumoricidal single-chain antibody against hepatocellular carcinoma

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    Imanaka Tadayuki

    2002-09-01

    Full Text Available Abstract Background Hep27 monoclonal (Hep27 Mab is an antibody against hepatocellular carcinoma. Hep27 Mab itself can inhibit the growth of a hepatocellular carcinoma cell line (HCC-S102. We attempted to produce a single-chain fragment (scFv, a small fragment containing an antigen-binding site of Hep27 Mab, by using DNA-recombinant techniques. Results The sequences encoding the variable regions of heavy (VH and light (VL chains of a murine Hep27 Mab were linked together by a linker peptide (Gly4Ser3 and tagged with a hexa-histidine at the C-terminal; the resultant DNA construct was expressed in E. coli as an insoluble protein. The denatured scFv was refolded and purified by immobilized metal ion affinity chromatography (12 mg/l with a molecular weight of 27 kDa. Hep27scFv exhibited a tumoricidal activity against the HCC-S102 cell as its parental antibody (Hep27 Mab. Conclusion This scFv may be a potential candidate for a targeting agent in HCC immunodiagnosis or immunotherapy.

  20. Non-transplant therapies for patients with hepatocellular carcinoma and Child-Pugh-Turcotte class B cirrhosis.

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    Granito, Alessandro; Bolondi, Luigi

    2017-02-01

    Underlying liver cirrhosis is present in most patients with hepatocellular carcinoma, and liver transplantation is the only treatment strategy to cure both diseases. All other hepatocellular carcinoma treatment strategies have to take into account residual liver function that concurs with the patient's prognosis and might limit their feasibility. In patients with hepatocellular carcinoma and Child-Pugh-Turcotte class B (CPT-B), owing to borderline liver function, any intervention might be offset by liver function deterioration. In this setting, the decision for hepatocellular carcinoma treatment requires a comprehensive assessment of liver function, not restricted to the CPT classification, in addition to a careful evaluation of the prognostic effect of hepatocellular carcinoma compared with cirrhosis. In this Review, we provide an overview of the literature regarding the benefits and harms of non-transplant therapies in patients with hepatocellular carcinoma and CPT-B cirrhosis.

  1. c-MET receptor tyrosine kinase as a molecular target in advanced hepatocellular carcinoma

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    Granito A

    2015-04-01

    Full Text Available Alessandro Granito,1 Elena Guidetti,1 Laura Gramantieri2,3 1Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna, Bologna, Italy; 2Dipartimento dell'Apparato Digerente, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 3Centro di Ricerca Biomedica Applicata (CRBA, Azienda Ospedaliero-Universitaria Policlinico S Orsola-Malpighi e Università di Bologna, Bologna, Italy Abstract: c-MET is the membrane receptor for hepatocyte growth factor (HGF, also known as scatter factor or tumor cytotoxic factor, a mitogenic growth factor for hepatocytes. HGF is mainly produced by cells of mesenchymal origin and it mainly acts on neighboring epidermal and endothelial cells, regulating epithelial growth and morphogenesis. HGF/MET signaling has been identified among the drivers of tumorigenesis in human cancers. As such, c-MET is a recognized druggable target, and against it, targeted agents are currently under clinical investigation. c-MET overexpression is a common event in a wide range of human malignancies, including gastric, lung, breast, ovary, colon, kidney, thyroid, and liver carcinomas. Despite c-MET overexpression being reported by a large majority of studies, no evidence for a c-MET oncogenic addiction exists in hepatocellular carcinoma (HCC. In particular, c-MET amplification is a rare event, accounting for 4%–5% of cases while no mutation has been identified in c-MET oncogene in HCC. Thus, the selection of patient subgroups more likely to benefit from c-MET inhibition is challenging. Notwithstanding, c-MET overexpression was reported to be associated with increased metastatic potential and poor prognosis in patients with HCC, providing a rationale for its therapeutic inhibition. Here we summarize the role of activated HGF/MET signaling in HCC, its prognostic relevance, and the implications for therapeutic approaches in HCC. Keywords: hepatocellular carcinoma, c-MET, clinical trials

  2. Antiviral therapy for hepatitis B virus-related hepatocellular carcinoma after surgery: A comment for moving forward

    Institute of Scientific and Technical Information of China (English)

    Jian-Hong; Zhong; Tian; Yang; Bang-De; Xiang; Le-Qun; Li; Liang; Ma

    2016-01-01

    Recurrence rate of hepatocellular carcinoma remains quite high even after surgery,and no postoperative therapies have been definitively shown to prevent hepatocellular carcinoma recurrence.A previous study showed that therapy with nucleos(t)ide analogues given to such patients after surgery significantly improved survival.However,many questions still exist about the usage of nucleos(t)ide analogues for patients with hepatocellular carcinoma after surgery.

  3. Computational Discovery of Niclosamide Ethanolamine, a Repurposed Drug Candidate That Reduces Growth of Hepatocellular Carcinoma Cells In Vitro and in Mice by Inhibiting Cell Division Cycle 37 Signaling.

    Science.gov (United States)

    Chen, Bin; Wei, Wei; Ma, Li; Yang, Bin; Gill, Ryan M; Chua, Mei-Sze; Butte, Atul J; So, Samuel

    2017-06-01

    Drug repositioning offers a shorter approval process than new drug development. We therefore searched large public datasets of drug-induced gene expression signatures to identify agents that might be effective against hepatocellular carcinoma (HCC). We searched public databases of messenger RNA expression patterns reported from HCC specimens from patients, HCC cell lines, and cells exposed to various drugs. We identified drugs that might specifically increase expression of genes that are down-regulated in HCCs and reduce expression of genes up-regulated in HCCs using a nonparametric, rank-based pattern-matching strategy based on the Kolmogorov-Smirnov statistic. We evaluated the anti-tumor activity of niclosamide and its ethanolamine salt (NEN) in HCC cell lines (HepG2, Huh7, Hep3B, Hep40, and PLC/PRF/5), primary human hepatocytes, and 2 mouse models of HCC. In one model of HCC, liver tumor development was induced by hydrodynamic delivery of a sleeping beauty transposon expressing an activated form of Ras (v12) and truncated β-catenin (N90). In another mouse model, patient-derived xenografts were established by implanting HCC cells from patients into livers of immunocompromised mice. Tumor growth was monitored by bioluminescence imaging. Tumor-bearing mice were fed a regular chow diet or a chow diet containing niclosamide or NEN. In a separate experiment using patient-derived xenografts, tumor-bearing mice were given sorafenib (the standard of care for patients with advanced HCC), NEN, or niclosamide alone; a combination of sorafenib and NEN; or a combination sorafenib and niclosamide in their drinking water, or regular water (control), and tumor growth was monitored. Based on gene expression signatures, we identified 3 anthelmintics that significantly altered the expression of genes that are up- or down-regulated in HCCs. Niclosamide and NEN specifically reduced the viability of HCC cells: the agents were at least 7-fold more cytotoxic to HCCs than primary

  4. Spinal cord compression secondary to bone metastases from hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Dinesh Chandra Doval; Komal Bhatia; Ashok Kumar Vaid; Keechelat Pavithran; Jai Bhagwan Sharma; Digant Hazarika; Amarnath Jena

    2006-01-01

    Bone metastases are rare in primary hepatocellular carcinoma (HCC). Spinal cord compression (SCC) due to bone metastases occur commonly in patients with lung and breast carcinomas, and metastatic HCC is an unusual cause of SCC. Spinal cord compression is an oncologic emergency and treatment delays can lead to irreversible consequences. Thus, the awareness that SCC could be a potential complication of bone metastases due to HCC is of significance in initiation of early treatment that can improve the quality of life and survival of the patients, if diagnosed earlier. This paper describes four cases of primary HCC with varied manifestations of SCC due to bone metastases. The first patient presented primarily with the symptoms of bone pains corresponding to the bone metastases sites rather than symptoms of associated hepatic pathology and eventually developed SCC. The second patient, diagnosed as having HCC, developed extradural SCC leading to paraplegia during the course of illness, for which he underwent emergency laminectomy with posterior fixation. The third patient developed SCC soon after the primary diagnosis and had to undergo emergency laminectomy. Post laminectomy he had good neurological recovery. The Fourth patient presented primarily with radicular pains rather than frank paraplegia as the first manifestation of SCC.

  5. Epigenetic inactivation of SLIT2 in human hepatocellular carcinomas.

    Science.gov (United States)

    Jin, Jie; You, Haiyan; Yu, Bin; Deng, Yun; Tang, Ning; Yao, Genfu; Shu, Huiqun; Yang, Shengli; Qin, Wenxin

    2009-01-30

    Recent findings have shown that SLIT2 appears to function as a novel tumor suppressor gene. In addition, hypermethylation of its promoter region has been detected in various cancers, including breast and lung cancer, colorectal carcinoma, and gliomas. Here, we report for the first time that there is epigenetic silencing of SLIT2 in human hepatocellular carcinoma (HCC). Downregulation of SLIT2 was detected in 6 of 8 (75%) HCC cell lines by quantitative real-time RT-PCR (qRT-PCR), and the downregulation of SLIT2 was generally dependent on the degree of methylation at the promoter region. Furthermore, expression of SLIT2 was restored in relatively low-expressing cell lines after treatment with 5-aza-2-deoxycytidine (5-Aza-dC). Downregulation of SLIT2 expression was also detected in 45 of 54 primary HCC samples (83.3%), and the decrease in expression was significantly correlated with CpG island hypermethylation. This decrease of SLIT2 expression was also associated with lymph node metastasis in HCC. Moreover, overexpression of SLIT2 in SMMC-7721 cells induced by recombinant adenovirus suppressed cell growth, migration, and invasion, These results suggest that epigenetic inactivation of SLIT2 in HCC may be important in the development and progression of HCC. Thus, SLIT2 may be useful as a therapeutic target in the treatment of HCC.

  6. Evaluation of Photoelectron Therapy Effect on Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    bahram Mofid

    2007-10-01

    Full Text Available Mofid B1, Navabpoor M2, Alizadeh Azimi M3 1. Assistant professor, Department of Radiotherapy, Faculty of Para-Medicine, Shahid Beheshti University of medical sciences 2. Instructor, Department of Technology of radiology, Faculty of Para-Medicine, Shahid Beheshti University of medical sciences Abstract Background: Photoelectron therapy method has been usad successfully, on the body phantom, cancer cells culture and animals. In this method, drugs containing x-Ray opaque factors–with high atomic numbers–are injected into the patient’s vein. After appropriate drug accumulation, about at least ten percent of the total injected amounts, 200kev. up to 300kev. of localized x-Ray beams is radiated to the site of the tumor. The Ethic Committee of Shahid Beheshti University of Medical Education and Health Services authorized the implementation of this new cancer treatment method, initially only on the group of patients who suffered from hepato-cellular carcinoma. Hepato cellular carcinoma is one of the most current malignancies of liver. In some cases, in addition to surgery, several approaches exist to come near the aim of predominating hepato-cellular carcinoma such as chemotherapy, current Radiation Therapy, Radio-Frequency application (RF, Trans-Artepical Chemo Embolization, (TACE, and Percutaneous Ethanol Injection (PEI. The effectiveness of the above-mentioned methods is about 10%-47%, applied alone or along side each other. Materials and methods: This study was a clinical-trial one. In this study, first, lipiodol (an x-ray opaque material with a high atomic number was transferred into the main vessel terminating to the tumor by angio-catheterization. Then,200kev. up to 250kev. of localized x-ray was radiated to the site of the tumor in one session. The drug volume was proportionally selected to the volume of the tumor, and the irradiation intensity was between 400 to 600cent.Gy. the beam energy absorption capacity of this drug is as times as

  7. Experimental evidence of Migfilin as a new therapeutic target of hepatocellular carcinoma metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Gkretsi, Vasiliki, E-mail: vasso.gkretsi@gmail.com [Department of Biomedical Research and Technology, Institute for Research and Technology-Thessaly, Centre for Research and Technology-Hellas (CE.R.T.H.), Larissa 41222 (Greece); Bogdanos, Dimitrios P. [Department of Biomedical Research and Technology, Institute for Research and Technology-Thessaly, Centre for Research and Technology-Hellas (CE.R.T.H.), Larissa 41222 (Greece); Department of Rheumatology, School of Medicine, University of Thessaly, University Hospital of Larissa, 41110 Larissa (Greece); Institute of Liver Studies, King' s College Hospital, Denmark Hill, London SE5 9RS (United Kingdom)

    2015-06-10

    Migfilin is a novel cell–matrix adhesion protein known to interact with Vasodilator Stimulated Phosphoprotein (VASP) and be localized both at cell–matrix and cell–cell adhesions. To date there is nothing known about its role in hepatocellular carcinoma (HCC). As matrix is important in metastasis, we aimed to investigate the Migfilin's role in HCC metastasis using two human HCC cell lines that differ in their metastatic potential; non-invasive Alexander cells and the highly invasive HepG2 cells. We silenced Migfilin by siRNA and studied its effect on signaling and metastasis-related cellular properties. We show that Migfilin's expression is elevated in HepG2 cells and its silencing leads to upregulation of actin reorganization-related proteins, namely phosphor-VASP (Ser157 and Ser239), Fascin-1 and Rho-kinase-1, promoting actin polymerization and inhibiting cell invasion. Phosphor-Akt (Ser473) is decreased contributing to the upregulation of free and phosphor-β-catenin (Ser33/37Thr41) and inducing proliferation. Migfilin elimination upregulates Extracellular Signal–regulated kinase, which increases cell adhesion in HepG2 and reduces invasiveness. This is the first study to reveal that Migfilin inhibition can halt HCC metastasis in vitro, providing the molecular mechanism involved and presenting Migfilin as potential therapeutic target against HCC metastasis. - Highlights: • Migfilin is a cell–matrix and cell–cell adhesion protein known to interact with VASP. • Nothing is known about Migfilin's role in hepatocellular carcinoma (HCC). • We eliminated Migfilin from 2 HCC cell lines and studied in vitro metastasis. • Its silencing inhibits cell invasion and promotes adhesion in HepG2 invasive cells. • We provide molecular mechanism by which Migfilin elimination halts HCC metastasis.

  8. ROCK is involved in vasculogenic mimicry formation in hepatocellular carcinoma cell line.

    Science.gov (United States)

    Zhang, Ji-Gang; Li, Xiao-Yu; Wang, Yu-Zhu; Zhang, Qi-Di; Gu, Sheng-Ying; Wu, Xin; Zhu, Guan-Hua; Li, Qin; Liu, Gao-Lin

    2014-01-01

    Ras homolog family member A (RhoA) and Rho-associated coiled coil-containing protein kinases 1 and 2 (ROCK1 and 2) are key regulators of focal adhesion, actomyosin contraction and cell motility. RhoA/ROCK signaling has emerged as an attractive target for the development of new cancer therapeutics. Whether RhoA/ROCK is involved in regulating the formation of tumor cell vasculogenic mimicry (VM) is largely unknown. To confirm this hypothesis, we performed in vitro experiments using hepatocellular carcinoma (HCC) cell lines. Firstly, we demonstrated that HCC cells with higher active RhoA/ROCK expression were prone to form VM channels, as compared with RhoA/ROCK low-expressing cells. Furthermore, Y27632 (a specific inhibitor of ROCK) rather than exoenzyme C3 (a specific inhibitor of RhoA) effectively inhibited the formation of tubular network structures in a dose-dependent manner. To elucidate the possible mechanism of ROCK on VM formation, real-time qPCR, western blot and immunofluorescence were used to detect changes of the key VM-related factors, including VE-cadherin, erythropoietin-producing hepatocellular carcinoma-A2 (EphA2), phosphoinositide 3-kinase (PI3K), matrix metalloproteinase (MMP)14, MMP2, MMP9 and laminin 5γ2-chain (LAMC2), and epithelial-mesenchymal-transition (EMT) markers: E-cadherin and Vimentin. The results showed that all the expression profiles were attenuated by blockage of ROCK. In addition, in vitro cell migration and invasion assays showed that Y27632 inhibited the migration and invasion capacity of HCC cell lines in a dose-dependent manner markedly. These data indicate that ROCK is an important mediator in the formation of tumor cell VM, and suggest that ROCK inhibition may prove useful in the treatment of VM in HCC.

  9. MicroRNA-124 suppresses growth of human hepatocellular carcinoma by targeting STAT3

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Yanxin [Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, Beijing 100191 (China); Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, Guangdong Province, Shenzhen 518036 (China); Yue, Xupeng [Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, Guangdong Province, Shenzhen 518036 (China); Cui, Yuanyuan [Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, Beijing 100191 (China); Zhang, Jufeng, E-mail: jfzhang111@163.com [Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, Guangdong Province, Shenzhen 518036 (China); Wang, KeWei, E-mail: wangkw@bjmu.edu.cn [Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, Beijing 100191 (China); Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, Guangdong Province, Shenzhen 518036 (China); Department of Molecular and Cellular Pharmacology, State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191 (China)

    2013-11-29

    Highlights: •miR-124 is down-regulated in hepatocellular carcinoma HepG2 cells. •Over-expression of miR-124 suppresses proliferation and induces apoptosis in HepG2 cells. •miR-124 inhibits xenograft tumor growth in nude mice implanted with HepG2 cells by reducing STAT3 expression. •STATs function as a novel target of miR-124 in HCC HepG2 cells. -- Abstract: The aberrant expression of microRNAs is associated with development and progression of cancers. Down-regulation of miR-124 has been demonstrated in the hepatocellular carcinoma (HCC), but the underlying mechanism by which miR-124 suppresses tumorigenesis in HCC remains elusive. In this study, we found that miR-124 suppresses the tumor growth of HCC through targeting the signal transducers and activators of transcription 3 (STAT3). Overexpression of miR-124 suppressed proliferation and induced apoptosis in HepG-2 cells. Luciferase assay confirmed that miR-124 binding to the 3′-UTR region of STAT3 inhibited the expression of STAT3 and phosphorylated STAT3 proteins in HepG-2 cells. Knockdown of STAT3 by siRNA in HepG-2 cells mimicked the effect induced by miR-124. Overexpression of STAT3 in miR-124-transfected HepG-2 cells effectively rescued the inhibition of cell proliferation caused by miR-124. Furthermore, miR-124 suppressed xenograft tumor growth in nude mice implanted with HepG-2 cells by reducing STAT3 expression. Taken together, our findings show that miR-124 functions as tumor suppressor in HCC by targeting STAT3, and miR-124 may therefore serve as a biomarker for diagnosis and therapeutics in HCC.

  10. Nanosecond pulsed electric field (nsPEF) treatment for hepatocellular carcinoma: a novel locoregional ablation decreasing lung metastasis.

    Science.gov (United States)

    Yin, Shengyong; Chen, Xinhua; Hu, Chen; Zhang, Xueming; Hu, Zhenhua; Yu, Jun; Feng, Xiaowen; Jiang, Kai; Ye, Shuming; Shen, Kezhen; Xie, Haiyang; Zhou, Lin; James Swanson, Robert; Zheng, Shusen

    2014-05-01

    Hepatocellular carcinoma (HCC) is a highly aggressive malignancy. Nanosecond pulsed electric field (nsPEF) is a new technology destroying tumor cells with a non-thermal high voltage electric field using ultra-short pulses. The study's aim was to evaluate the ablation efficacy of nsPEFs with human HCC cell lines and a highly metastatic potential HCC xenograft model on BALB/c nude mice. The in vivo study showed nsPEFs induced HCC cell death in a dose dependent manner. On the high metastatic hepatocellular carcinoma cell line (HCCLM3) xenograft mice model, tumor growth was inhibited significantly in nsPEF-treated- groups (single dose and multi-fractionated dose). Besides a local effect, the nsPEF treatment reduced pulmonary metastases. The nsPEFs also enhanced HCC cell phagocytosis by human macrophage cell (THP1) in vitro. The nsPEF is efficient in controlling HCC progression and reducing its metastasis. NsPEF treatment may elicit a host immune response against tumor cells. This study suggests nsPEF therapy could be used as a potential locoregional therapy for hepatocellular carcinoma.

  11. Effect of TSLC1 Gene on Proliferation, Invasion and Apoptosis of Human Hepatocellular Carcinoma Cell Line HepG2

    Institute of Scientific and Technical Information of China (English)

    QIN Li; ZHU Wentao; XU Tao; HAO Youhua; ZHANG Zhengmao; TIAN Yongjun; YANG Dongliang

    2007-01-01

    The recombinant plasmid pCI-TSLC1 carrying TSLC1 gene was stably transfected into human hepatocellular carcinoma cell line HepG2. Cell proliferation was analyzed by MTT assay. The ability of migration was determined by transwell and FACSort flow cytometry was used to detect the cell cycle distribution and apoptosis. Western blotting revealed that H4 expressed higher amounts of TSLC1 protein than H15 and H0 did. The growth of TSLC1-transfected cells was significantly sup- pressed in vitro, and the ability of migration was reduced as well. The re-expression of TSLC1 could induce cell apoptosis. It was concluded that TSLC1 strongly inhibited the growth and ability of mi- gration of HepG2 cell line in vitro and also induced apoptosis, suggesting that TSLC1 could reduce the tumorigenicity of human hepatocellular carcinoma cell line HepG2 in vitro, which provided a ba-sis for further exploring the roles of TSLC1 in hepatocellular cellular carcinoma.

  12. Effects of AFP gene silencing on apoptosis and proliferation of a hepatocellular carcinoma cell line.

    Science.gov (United States)

    Zhang, Ling; He, Tao; Cui, Hong; Wang, Yunjian; Huang, Changshan; Han, Feng

    2012-08-01

    Alpha fetoprotein (AFP) is an oncoembryonal protein that is highly expressed in the majority of hepatocellular carcinomas. Previous studies have shown that AFP may be involved in multiple cell growth regulating, differentiating, and immunosuppressive activities. We investigated the effects of AFP gene silencing by siRNA on apoptosis and proliferation of hepatocellular carcinoma cell line EGHC-9901, which highly expresses AFP and may serve as an ideal model for investigation of AFP functions. siRNA expressing plasmid targeting the AFP gene was first established and subsequently transfected into hepatocellular carcinoma cell line EGHC-9901; cells were then divided into three groups: siRNA-afp, transfected with AFP-siRNA; siRNA-beta-actin, transfected with siRNA-beta-actin as the positive group; and vector control, transfected with empty vector as the blank control group. After G418 positive clone selection for a couple of weeks, Western blot and RT (reverse transcription)-PCR assay demonstrated that AFP expression was almost completely inhibited by siRNA-afp, which indicates that siRNA expressing plasmid targeting the AFP gene has been successfully established. Furthermore, MTT (methyl thiazolyl tetrazelium) assay showed that cells transfected with siRNA-afp proliferated at a significantly lower speed than the other two groups and flat plate clone formation assay also witnessed less clones with diameters of more than 75 μm in siRNA-afp immunofluorescence indicating that the apoptosis rate of cells transfected with siRNA-afp was significantly higher than the other two groups. Furthermore, flow cytometry manifested approximately 20% more cells of siRNA-afp within G1 phase than those of the negative group, indicating that inhibition of AFP expression may cause G1 phase arrest. Finally, Western blot and RT-PCR assay demonstrated that siRNA-afp induced a higher expression of caspase-3 than the other two groups whereas there was no difference in expression of caspase-8

  13. Cyclooxygenase-2 inhibitor is a robust enhancer of anticancer agents against hepatocellular carcinoma multicellular spheroids

    Directory of Open Access Journals (Sweden)

    Cui J

    2014-02-01

    Full Text Available Jie Cui,1,2 Ya-Huan Guo,3 Hong-Yi Zhang,4 Li-Li Jiang,1 Jie-Qun Ma,1 Wen-Juan Wang,1 Min-Cong Wang,1 Cheng-Cheng Yang,1 Ke-Jun Nan,1 Li-Ping Song5 1Department of Oncology, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, 2Department of Oncology, Yan'an University Affiliated Hospital, Yan'an, 3Department of Oncology, Shaanxi Province Cancer Hospital, Xi'an, 4Department of Urology, Yan'an University Affiliated Hospital, Yan'an, 5Department of Radiotherapy, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, People's Republic of China Purpose: Celecoxib, an inhibitor of cyclooxygenase-2 (COX2, was investigated for enhancement of chemotherapeutic efficacy in cancer clinical trials. This study aimed to determine whether celecoxib combined with 5-fluorouracil or sorafenib or gefitinib is beneficial in HepG2 multicellular spheroids (MCSs, as well as elucidate the underlying mechanisms. Methods: The human hepatocellular carcinoma cell line HepG2 MCSs were used as in vitro models to investigate the effects of celecoxib combined with 5-fluorouracil or sorafenib or gefitinib treatment on cell growth, apoptosis, and signaling pathway. Results: MCSs showed resistance to drugs compared with monolayer cells. Celecoxib combined with 5-fluorouracil or sorafenib exhibited a synergistic action. Exposure to celecoxib (21.8 µmol/L plus 5-fluorouracil (8.1 × 10-3 g/L or sorafenib (4.4 µmol/L increased apoptosis but exerted no effect on COX2, phosphorylated epidermal growth-factor receptor (p-EGFR and phosphorylated (p-AKT expression. Gefitinib (5 µmol/L, which exhibits no growth-inhibition activity as a single agent, increased the inhibitory effect of celecoxib. Gefitinib (5 µmol/L plus celecoxib (21.8 µmol/L increased apoptosis. COX2, p-EGFR, and p-AKT were inhibited. Conclusion: Celecoxib combined with 5-fluorouracil or sorafenib or gefitinib may be superior to single-agent therapy in HepG2

  14. The relationship between the hepatitis B virus base core and precore/core promoter mutations and the development of cirrhotic hepatocellular carcinoma and noncirrhotic hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    徐尧江

    2013-01-01

    Objective To investigate the mutations of basal core promoter(BCP) and precore(PreC) region of hepatitis B virus(HBV) and the association with the development of hepatocellular carcinoma in patients with chronic HBV infection. Methods Totally 381 untreated HBV patients were recruited from the Department of Infectious

  15. Enhanced radioimmunotherapeutic efficacy of a monoclonal antibody cocktail against SMMC—7721 human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    SONGYIQIANG; GENFENGWANG; 等

    1998-01-01

    The improved tumoricidal effect of the radioantibody mixture (“cocktail”)has been reported recently for the treatment of colon tumor.In the present study,we demonstrated the enhanced radioimmunotherapeutic efficacy of a monoclonal antibody (MAb) cocktail against human hepatocellular carcinoma.Therapeutic efficacy was determined by measuring the change in tumor size over a period,determining the percentage of growth inhibition of each treatment at various times after radioantibody therapy.Radioimmunotherapy of SMMC-7721 human hepatoma xenografts in athymic unde mice with combination of 131Ilabeled Hepama-1 and 131 I-labeled 9403 mouse MAbs was more effective than using either Hepeam-1 or 9403 MAb alone The MAb cocktail could target a greater number of hepatoma cells and increase the magnitude of hepatoma cell uptake of radioantibodies.The in vitro results explain the enhanced effect of the MAb cocktail in in vivo model system.

  16. Antiproliferative effects of Ceratonia siliqua L. on mouse hepatocellular carcinoma cell line.

    Science.gov (United States)

    Corsi, L; Avallone, R; Cosenza, F; Farina, F; Baraldi, C; Baraldi, M

    2002-12-01

    Extracts from pods and leaves of carob (Ceratonia siliqua L.) were tested for their ability to inhibit cell proliferation of mouse hepatocellular carcinoma cell line (T1). The two extracts showed a marked alteration of T1 cell proliferation in a dose-related fashion reaching the maximal effect at 1 mg/ml. Moreover, we demonstrated that leaf and pod extracts were able to induce apoptosis in T1 cell lines after 24-h treatment mediating a direct activation of the caspase 3 pathway. HPLC analysis revealed the presence of gallic acid, (-) epigallocatechin-3-gallate and (-) epicatechin-3-gallate in pod and leaf extracts, compounds well known to exert antiproliferative effects. Their concentration reached 6.28 mg/g in carob leaves and 1.36 mg/g in carob pods extract. The discovery that carob pod and leaf extracts contained antiproliferative agents could be of practical importance in the development of functional foods and/or chemopreventive drugs.

  17. Prp19 Arrests Cell Cycle via Cdc5L in Hepatocellular Carcinoma Cells

    Science.gov (United States)

    Huang, Renzheng; Xue, Ruyi; Qu, Di; Yin, Jie; Shen, Xi-Zhong

    2017-01-01

    Pre-mRNA processing factor 19 (Prp19) is involved in many cellular events including pre-mRNA processing and DNA damage response. Recently, it has been identified as a candidate oncogene in hepatocellular carcinoma (HCC). However, the role of Prp19 in tumor biology is still elusive. Here, we reported that Prp19 arrested cell cycle in HCC cells via regulating G2/M transition. Mechanistic insights revealed that silencing Prp19 inhibited the expression of cell division cycle 5-like (Cdc5L) via repressing the translation of Cdc5L mRNA and facilitating lysosome-mediated degradation of Cdc5L in HCC cells. Furthermore, we found that silencing Prp19 induced cell cycle arrest could be partially resumed by overexpressing Cdc5L. This work implied that Prp19 participated in mitotic progression and thus could be a promising therapeutic target of HCC. PMID:28387715

  18. Prp19 Arrests Cell Cycle via Cdc5L in Hepatocellular Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Renzheng Huang

    2017-04-01

    Full Text Available Pre-mRNA processing factor 19 (Prp19 is involved in many cellular events including pre-mRNA processing and DNA damage response. Recently, it has been identified as a candidate oncogene in hepatocellular carcinoma (HCC. However, the role of Prp19 in tumor biology is still elusive. Here, we reported that Prp19 arrested cell cycle in HCC cells via regulating G2/M transition. Mechanistic insights revealed that silencing Prp19 inhibited the expression of cell division cycle 5-like (Cdc5L via repressing the translation of Cdc5L mRNA and facilitating lysosome-mediated degradation of Cdc5L in HCC cells. Furthermore, we found that silencing Prp19 induced cell cycle arrest could be partially resumed by overexpressing Cdc5L. This work implied that Prp19 participated in mitotic progression and thus could be a promising therapeutic target of HCC.

  19. Over-expression of LPTS-L in hepatocellular carcinoma cell line SMMC-7721 induces crisis

    Institute of Scientific and Technical Information of China (English)

    Cheng Liao; Mu-Jun Zhao; Jing Zhao; Di Jia; Hai Song; Zai-Ping Li

    2002-01-01

    AIM: To evaluate the function of the longer transcripts LPTS-Lin hepatocellular carcinoma cell line SMMC-7721.METHODS: SMMC-7721 cells were transfected with LPTSL expression construct and stably transfected cells were selected by G418. Multiple single clones formed and were checked for their phenotype. In the study of the effect on telomerase activity of LPTS-Lin vitro, GST-LPTS-L fusion protein was expressed in E.coli and purified by glutathioneagarose column. Telomeric repeat amplification protocol (TRAP) assays were performed to study the influence of telomerase activity in SMMC-7721 cells.RESULTS: Over-expression of LPTS-L induced SMMC-7721 cells into crisis. LPTS-L could inhibit the telomerase activity in SMMC-7721 cellsin vitro.CONCLUSION: LPTS-L is a potent telomeraseinhibitor. Over-expression of LPTS-L can induce hepatoma cells into crisis due to the reduction of telomerase activity.

  20. Factors Predicting Survival after Transarterial Chemoembolization of Unresectable Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Farina M. Hanif

    2014-10-01

    Full Text Available Background: Transarterial chemoembolization is the preferred treatment for unresectable, intermediate-stage hepatocellular carcinoma. Survival after transarterial chemoembolization can be highly variable. The purpose of this study is to identify the factors that predict overall survival of patients with unresectable hepatocellular carcinoma who undergo transarterial chemoembolization as the initial therapy. Methods:We included patients who underwent transarterial chemoembolization from 2007 to 2012 in this study. Patient’s age, gender, cause of cirrhosis, Child-Turcotte-Pugh score, model of end-stage liver disease score, Cancer of the Liver Italian Program score, Okuda stage, alpha- fetoprotein level, site, size and number of tumors were recorded. Radiological response to transarterial chemoembolization was assessed by computerized tomography scan at 1 and 3 months after the procedure. Repeat sessions of transarterial chemoembolization were performed according to the response. We performed survival assessment and all patients were assessed for survival at the last follow-up. Results: Included in this study were 71 patients of whom there were 57 (80.3 % males, with a mean age of 51.9±12.1 years (range: 18-76 years. The mean follow-up period was 12.5±10.7 months. A total of 31 (43.7% patients had only one session of transarterial chemoembolization, 17 (23.9% underwent 2 and 11 (15.5% had 3 or more sessions. On univariate analysis, significant factors that predicted survival included serum bilirubin (P=0.02, esophageal varices (P=0.002, Cancer of the Liver Italian Program score (P=0.003, tumor size (P=0.005, >3 sessions of transarterial chemoembolization (P=0.006 and patient's age (P=0.001. Cox regression analysis showed that tumor size of 1 transarterial chemoembolization session (P=0.004 were associated with better survival. Conclusion: Our study demonstrates that survival after transarterial chemoem- bolization is predicted by tumor size

  1. Leptin signaling molecular actions and drug target in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Jiang N

    2014-11-01

    Full Text Available Nan Jiang,1,* Rongtong Sun,2,* Qing Sun3 1Shandong University School of Medicine, Jinan, Shandong Province, People’s Republic of China; 2Weihai Municipal Hospital, Weihai, Shandong Province, People’s Republic of China; 3Department of Pathology, QianFoShan Hospital Affiliated to Shandong University, Jinan, Shandong Province, People’s Republic of China *These authors contributed equally to this work Abstract: Previous reports indicate that over 13 different tumors, including hepatocellular carcinoma (HCC, are related to obesity. Obesity-associated inflammatory, metabolic, and endocrine mediators, as well as the functioning of the gut microbiota, are suspected to contribute to tumorigenesis. In obese people, proinflammatory cytokines/chemokines including tumor necrosis factor-alpha, interleukin (IL-1 and IL-6, insulin and insulin-like growth factors, adipokines, plasminogen activator inhibitor-1, adiponectin, and leptin are found to play crucial roles in the initiation and development of cancer. The cytokines induced by leptin in adipose tissue or tumor cells have been intensely studied. Leptin-induced signaling pathways are critical for biological functions such as adiposity, energy balance, endocrine function, immune reaction, and angiogenesis as well as oncogenesis. Leptin is an activator of cell proliferation and anti-apoptosis in several cell types, and an inducer of cancer stem cells; its critical roles in tumorigenesis are based on its oncogenic, mitogenic, proinflammatory, and pro-angiogenic actions. This review provides an update of the pathological effects of leptin signaling with special emphasis on potential molecular mechanisms and therapeutic targeting, which could potentially be used in future clinical settings. In addition, leptin-induced angiogenic ability and molecular mechanisms in HCC are discussed. The stringent binding affinity of leptin and its receptor Ob-R, as well as the highly upregulated expression of both

  2. Emerging role of Hpo signaling and YAP in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Valero V III

    2015-06-01

    Full Text Available Vicente Valero III,1 Timothy M Pawlik,1 Robert A Anders21Department of Surgery, Division of Surgical Oncology, 2Department of Pathology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USAAbstract: Hepatocellular carcinoma (HCC is the sixth most common cancer and the third most common cause of cancer-related mortality worldwide. Due to the poor prognosis and limited therapeutic options, there is great interest in further understanding better the molecular underpinnings and potential molecular targets associated with HCC. The Hippo (Hpo signaling pathway and YAP, its principal downstream effector, represent an innovative area of research in HCC. Pioneered in Drosophila melanogaster, the Hpo cascade controls tissue homeostasis including organ size, cell proliferation, apoptosis, as well as cell-cycle regulation and differentiation. This conserved kinase cascade in mammals depends on central control by the tumor suppressor mammalian sterile 20-like kinase 1/2 (Mst1/2. The Mst1/2 commences the downstream kinase cascade, ultimately activating the oncoprotein YAP and allowing its physical association with downstream targets to enhance the gene expression signatures that are involved in proliferation and survival. Alterations in YAP expression and defective regulation of other key Hpo pathway members, such as Mst1/2, Salvador, neurofibromatosis and Mer (Nf2/mer, large tumor suppressor homolog 1/2 (Lats1/2, and Mps one binder kinase activator-like 1A and 1B (Mob1 drive carcinogenesis in animal models. The dysregulation of the Hpo pathway – resulting in an unchecked activation of YAP – culminates in the development of a broad range of human tumor types, including HCC. The abrogation of Mst1/2-mediated YAP phosphorylation permits YAP entry into the nucleus in murine models and functions similarly in human HCCs. Chemoresistance mechanisms displayed by HCC tumors occur in a YAP-dependent manner. The HCC specimens

  3. Recent Developments of c-Met as a Therapeutic Target in Hepatocellular Carcinoma.

    Science.gov (United States)

    Bouattour, Mohamed; Raymond, Eric; Qin, Shukui; Cheng, Ann-Lii; Stammberger, Uz; Locatelli, Giuseppe; Faivre, Sandrine

    2017-09-01

    Aberrant c-Met activity is implicated in the development of hepatocellular carcinoma (HCC), suggesting that c-Met inhibition may have therapeutic potential. However, clinical trials of nonselective kinase inhibitors with c-Met activity (tivantinib, cabozantinib, foretinib, and golvatinib) in patients with HCC have failed so far to demonstrate significant efficacy. This is likely due to several factors, including trial design, lack of patient selection according to tumor c-Met status, and the prevalent off-target activity of these agents, which may mean that c-Met inhibition is incomplete. In contrast, selective c-Met inhibitors (tepotinib, capmatinib) can be dosed at a level predicted to achieve a complete inhibition of tumor c-Met activity. Moreover, results from early trials can be used to optimize the design of clinical trials of these agents. Preliminary results suggest that selective c-Met inhibitors have antitumor activity in HCC, with acceptable safety and tolerability in patients with Child-Pugh A liver function. Ongoing trials have been designed to assess the efficacy and safety of selective c-Met inhibition compared with standard therapy in patients with HCC selected based on tumor c-Met status. Thus, c-Met inhibition continues to be an active area of research in HCC, with well-designed trials in progress to investigate the benefit of selective c-Met inhibitors. This article is protected by copyright. All rights reserved. © 2017 by the American Association for the Study of Liver Diseases.

  4. Anticancer effects of deproteinized asparagus polysaccharide on hepatocellular carcinoma in vitro and in vivo.

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    Xiang, Jianfeng; Xiang, Yanjie; Lin, Shengming; Xin, Dongwei; Liu, Xiaoyu; Weng, Lingling; Chen, Tao; Zhang, Minguang

    2014-04-01

    Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies in the world whose chemoprevention became increasingly important in HCC treatment. Although the anticancer effects of asparagus constituents have been investigated in several cancers, its effects on hepatocellular carcinoma have not been fully studied. In this study, we investigated the anticancer effects of the deproteinized asparagus polysaccharide on the hepatocellular carcinoma cells using the in vitro and in vivo experimental model. Our data showed that deproteinized asparagus polysaccharide might act as an effective inhibitor on cell growth in vitro and in vivo and exert potent selective cytotoxicity against human hepatocellular carcinoma Hep3B and HepG2 cells. Further study showed that it could potently induce cell apoptosis and G2/M cell cycle arrest in the more sensitive Hep3B and HepG2 cell lines. Moreover, deproteinized asparagus polysaccharide potentiated the effects of mitomycin both in vitro and in vivo. Mechanistic studies revealed that deproteinized asparagus polysaccharide might exert its activity through an apoptosis-associated pathway by modulating the expression of Bax, Bcl-2, and caspase-3. In conclusion, deproteinized asparagus polysaccharide exhibited significant anticancer activity against hepatocellular carcinoma cells and could sensitize the tumoricidal effects of mitomycin, indicating that it is a potential therapeutic agent (or chemosensitizer) for liver cancer therapy.

  5. Novel Altered Region for Biomarker Discovery in Hepatocellular Carcinoma (HCC Using Whole Genome SNP Array

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    Esraa M. Hashem

    2016-04-01

    Full Text Available cancer represents one of the greatest medical causes of mortality. The majority of Hepatocellular carcinoma arises from the accumulation of genetic abnormalities, and possibly induced by exterior etiological factors especially HCV and HBV infections. There is a need for new tools to analysis the large sum of data to present relevant genetic changes that may be critical for both understanding how cancers develop and determining how they could ultimately be treated. Gene expression profiling may lead to new biomarkers that may help develop diagnostic accuracy for detecting Hepatocellular carcinoma. In this work, statistical technique (discrete stationary wavelet transform for detection of copy number alternations to analysis high-density single-nucleotide polymorphism array of 30 cell lines on specific chromosomes, which are frequently detected in Hepatocellular carcinoma have been proposed. The results demonstrate the feasibility of whole-genome fine mapping of copy number alternations via high-density single-nucleotide polymorphism genotyping, Results revealed that a novel altered chromosomal region is discovered; region amplification (4q22.1 have been detected in 22 out of 30-Hepatocellular carcinoma cell lines (73%. This region strike, AFF1 and DSPP, tumor suppressor genes. This finding has not previously reported to be involved in liver carcinogenesis; it can be used to discover a new HCC biomarker, which helps in a better understanding of hepatocellular carcinoma.

  6. Plasma Level of Interleukin-35 as an Independent Prognostic Indicator in Hepatocellular Carcinoma.

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    Qiu, Xiangting; Wang, Xinhua; Song, Yucui; Chen, Lingling

    2016-12-01

    Hepatocellular carcinoma is a major type of liver cancer with poor prognosis. The aim of the study was to determine the prognostic significance of plasma interleukin-35 level in hepatocellular carcinoma. A total of 153 hepatocellular carcinoma patients and 153 healthy controls were enrolled. Blood samples were obtained at admission. Plasma interleukin-35 level was analyzed by enzyme-linked immunosorbent assay. Distribution of T cell subset and expression of Fas/FasL protein were detected by flow cytometry. The patients were followed up for 2 years. Poor prognosis was defined as death of hepatocellular carcinoma. The plasma levels of interleukin-35 were significantly higher in the patients than the controls (25.1 ± 13.1, 9.3 ± 6.3 pg/mL, P interleukin-35 (≥25.0 pg/mL) was associated with the poor prognosis in the patients (OR 6.63, 95 % CI 3.27-13.47). Compared with the patients with low level of interleukin-35 (interleukin-35 showed higher frequencies of CD4+CD25+FoxP3+ and CD3+Foxp3+ regulatory T cells (P interleukin-35 concentration might be an independent prognostic indicator in hepatocellular carcinoma. Such prognostic significance could be partly involved in the activation of regulatory T cell and the apoptosis of CD8+ T cell.

  7. Immunological Microenvironment of Hepatocellular Carcinoma and Its Clinical Implication.

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    Nishida, Naoshi; Kudo, Masatoshi

    2017-01-01

    Despite recent advances in the treatment of hepatocellular carcinoma (HCC), the prognosis of patients with advanced stage of disease remains unfavorable. Several immune therapies have been applied to HCC, and their responses have not been satisfactory. The immune response to cancer is determined by the balance between the antigenicity of the tumor and the microenvironment of cancer tissues. Generally, accumulated genetic mutations are observed in HCC, which may lead to increased neoantigens on cancer cells with high antigenicity. However, cancer cells may evade the immune system because of alterations in molecules and cellular pathways involved in antigen processing and presentation. In addition, hypoxia in tissue induces several cytokines, chemokines, and immunosuppressive molecules from HCC cells and stromal cells. These cells also produce cytokines that attract regulatory T cells infiltrating tumor tissues and contribute to establishing an immunosuppressive microenvironment. Some cancers show a good response to immune checkpoint therapy. However, prolonged stabilization of disease for this treatment is reportedly 12-41% in patients with advanced cancer. Therefore, immunosuppressive forces in the microenvironment of HCC may cause resistance to immune therapy, and modification of the tumor microenvironment may restore normal anticancer immunity. In this review, we focus on the immunological microenvironment of HCC tissues and discuss how the immunosuppressive environment of HCC should be modulated to achieve a favorable response to immune therapy, such as immune checkpoint therapy, in HCC. © 2016 S. Karger AG, Basel.

  8. Aided Diagnosis of Hepatocellular Carcinoma Using Serum Fucosylated Haptoglobin Ratios

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    Shang, Shuxin; Li, Wei; Qin, Xue; Zhang, Shu; Liu, Yinkun

    2017-01-01

    Aberrant fucosylation plays a functional role in regulating ontogeny and celluar differentiation and are differentially regulated in cancerous condition, which could provide hallmarks for cancer diagnostics and surveillance. We previously developed a magnetic beads-based lectin ELISA system to measure fucosylated haptoglobin (Hp), which has been reported to be a cancer biomarker through a series of glycoproteomic analysis. In this study, serum fucosylated Hp ratios were measured using our ELISA kit in a separate cohort of 260 patients independently, including 130 healthy controls and 130 patients with hepatocellular carcinoma (HCC). Fucosylated Hp /Hp ratio (levels of fucosylated Hp /levels of protein Hp) and ELISA Index (OD value of fucosylated Hp /OD value of protein Hp) were calculated respectively to reflect Hp fucosylation level on its protein level. Our data showed that fucosylated Hp /Hp ratio (AUC=0.8449) and ELISA Index (AUC=0.8581) had better performance in distinguishing HCC from controls, which indicated that fucosylated Hp ratios could improve the diagnosis and prediction of HCC even with a low level of alpha-fetoprotein (AFP). Additionally, the combination analysis of AFP and fucosylated Hp ratios increased the AUC value for HCC diagnosis. PMID:28382152

  9. Advantage of autologous blood transfusion in surgery for hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Yoshito Tomimaru; Hiroaki Nagano; Hidetoshi Eguchi; Shigeru Marubashi; Hiroshi Wada; Shogo Kobayashi; Masahiro Tanemura; Koji Umeshita; Yuichiro Doki; Masaki Mori

    2011-01-01

    AIM: To evaluate the significance of autologous blood transfusion (AT) in reducing homologous blood trans-fusion (HT) in surgery for hepatocellular carcinoma (HCC).METHODS: The proportion of patients who received HT was compared between two groups determined by the time of AT introduction; period A (1991-1994, n = 93) and period B (1995-2000, n = 201). Multivariate logistic regression analysis was performed in order to identify independent significant predictors of the need for HT. We also investigated the impact of AT and HT on long-term postoperative outcome after curative sur-gery for HCC.RESULTS: The proportion of patients with HT was significantly lower in period B than period A (18.9% vs 60.2%, P < 0.0001). Multivariate logistic regression analysis identified AT administration as a significant independent predictor of the need for HT (P < 0.0001). Disease-free survival in patients with AT was com-parable to that without any transfusion. Multivariate analysis identified HT administration as an independent significant factor for poorer disease-free survival (P = 0.0380).CONCLUSION: AT administration significantly de-creased the need for HT. Considering the postoperative survival disadvantage of HT, AT administration could improve the long-term outcome of HCC patients.

  10. Multidisciplinary perspective of hepatocellular carcinoma: A Pacific Northwest experience.

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    Yeh, Matthew M; Yeung, Raymond S; Apisarnthanarax, Smith; Bhattacharya, Renuka; Cuevas, Carlos; Harris, William P; Hon, Tony Lim Kiat; Padia, Siddharth A; Park, James O; Riggle, Kevin M; Daoud, Sayed S

    2015-06-18

    Hepatocellular carcinoma (HCC) is the most rapidly increasing type of cancer in the United States. HCC is a highly malignant cancer, accounting for at least 14000 deaths in the United States annually, and it ranks third as a cause of cancer mortality in men. One major difficulty is that most patients with HCC are diagnosed when the disease is already at an advanced stage, and the cancer cannot be surgically removed. Furthermore, because almost all patients have cirrhosis, neither chemotherapy nor major resections are well tolerated. Clearly there is need of a multidisciplinary approach for the management of HCC. For example, there is a need for better understanding of the fundamental etiologic mechanisms that are involved in hepatocarcinogenesis, which could lead to the development of successful preventive and therapeutic modalities. It is also essential to define the cellular and molecular bases for malignant transformation of hepatocytes. Such knowledge would: (1) greatly facilitate the identification of patients at risk; (2) prompt efforts to decrease risk factors; and (3) improve surveillance and early diagnosis through diagnostic imaging modalities. Possible benefits extend also to the clinical management of this disease. Because there are many factors involved in pathogenesis of HCC, this paper reviews a multidisciplinary perspective of recent advances in basic and clinical understanding of HCC that include: molecular hepatocarcinogenesis, non-invasive diagnostics modalities, diagnostic pathology, surgical modality, transplantation, local therapy and oncological/target therapeutics.

  11. Adrenal metastasis as first presentation of hepatocellular carcinoma

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    Zacharakis Evangelos

    2005-07-01

    Full Text Available Abstract Background Metastases from hepatocellular carcinoma (HCC can be found in the lung and adrenal gland. We report case of a patient who presented with adrenal metastasis as the first clinical manifestation of HCC. Case presentation A patient was referred for surgical treatment for a tumor in retro-peritoneal space. The computerized tomography (CT scan revealed a mass originating from the left adrenal gland. The patient underwent left adrenalectomy and the exploration of abdominal cavity did not reveal any other palpable lesions. Histologically, the resected lesion was a poorly differentiated metastatic tumor from HCC. Seven months later patient was readmitted complaining of cachexia, icterus, and significant weight loss. CT scan revealed hyperdense lesions of the liver Conclusion HCC may have atypical presentations like in present case. Fine needle aspiration/tru-cut® biopsy might be useful in the investigation of an accidentally discovered adrenal mass regardless of the size and can lead to the detection of a primary tumor.

  12. Clinical studies of hepatocellular carcinoma with liver cirrhosis and ascites.

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    Yuasa,Shiro

    1984-06-01

    Full Text Available A comparison was made of the clinical findings of 59 patients with liver cirrhosis (LC accompanied with hepatocellular carcinoma (HCC (of which 35 had ascites and 24 did not at the time of admission and 164 patients with LC, but without HCC (of which 39 had ascites and 125 did not. HCC patients were older and more often had hepatomegaly, vascular spider and pleural effusion than LC patients. Ascites was more frequently observed in HCC than in LC patients when the serum albumin level and the indocyanine green disappearance rate were relatively well maintained and when peripheral edema was absent. There was no difference in the ascitic protein concentration between LC and HCC patients. Malignant cells were detected in ascites only in 14% of the HCC patients. These facts indicate the presence of ascites-inducing factors in HCC patients which have no direct relation to serum colloid osmotic pressure and effective hepatic blood flow. Almost all of the HCC patients with ascites (96% died with ascites, whereas 54% of the LC patients with ascites recovered from the ascitic condition.

  13. Aberrant regulation of Wnt signaling in hepatocellular carcinoma

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    Liu, Li-Juan; Xie, Shui-Xiang; Chen, Ya-Tang; Xue, Jing-Ling; Zhang, Chuan-Jie; Zhu, Fan

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most lethal malignancies in the world. Several signaling pathways, including the wingless/int-1 (Wnt) signaling pathway, have been shown to be commonly activated in HCC. The Wnt signaling pathway can be triggered via both catenin β1 (CTNNB1)-dependent (also known as “canonical”) and CTNNB1-independent (often referred to as “non-canonical”) pathways. Specifically, the canonical Wnt pathway is one of those most frequently reported in HCC. Aberrant regulation from three complexes (the cell-surface receptor complex, the cytoplasmic destruction complex and the nuclear CTNNB1/T-cell-specific transcription factor/lymphoid enhancer binding factor transcriptional complex) are all involved in HCC. Although the non-canonical Wnt pathway is rarely reported, two main non-canonical pathways, Wnt/planar cell polarity pathway and Wnt/Ca2+ pathway, participate in the regulation of hepatocarcinogenesis. Interestingly, the canonical Wnt pathway is antagonized by non-canonical Wnt signaling in HCC. Moreover, other signaling cascades have also been demonstrated to regulate the Wnt pathway through crosstalk in HCC pathogenesis. This review provides a perspective on the emerging evidence that the aberrant regulation of Wnt signaling is a critical mechanism for the development of HCC. Furthermore, crosstalk between different signaling pathways might be conducive to the development of novel molecular targets of HCC. PMID:27672271

  14. Family history influences the early onset of hepatocellular carcinoma

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    Park, Chung-Hwa; Jeong, Seung-Hee; Yim, Hyeon-Woo; Kim, Jin Dong; Bae, Si Hyun; Choi, Jong Young; Yoon, Seung Kew

    2012-01-01

    AIM: To evaluate the relationship between a positive family history of primary liver cancer and hepatocellular carcinoma (HCC) development in Korean HCC patients. METHODS: We studied a total of 2242 patients diagnosed with HCC between January 1990 and July 2008, whose family history of primary liver cancer was clearly described in the medical records. RESULTS: Of the 2242 patients, 165 (7.4%) had a positive family history of HCC and 2077 (92.6%) did not. The male to female ratio was 3.6:1, and the major causes of HCC were chronic hepatitis B virus (HBV) infection in 75.1%, chronic hepatitis C virus infection in 13.2% and alcohol in 3.1%. The median ages at diagnosis in the positive- and negative-history groups were 52 years (range: 29-79 years) and 57 years (range: 18-89 years), respectively (P < 0.0001). Furthermore, among 1713 HCC patients with HBV infection, the number of patients under 45 years of age out of 136 patients with positive family history was 26 (19.1%), whereas those out of 1577 patients with negative family history was 197 (12.5%), suggesting that a positive family history may be associated with earlier development of HCC in the Korean population (P = 0.0028). CONCLUSION: More intensive surveillance maybe recommended to those with a positive family history of HCC for earlier diagnosis and proper management especially when HBV infection is present. PMID:22690075

  15. Occult HBV infection among Egyptian hepatocellular carcinoma patients

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    Mansor Tarek M

    2011-03-01

    Full Text Available Abstract Background Occult HBV infection accelerates the progression of liver fibrosis, cirrhosis, and finally leading to hepatocellular carcinoma (HCC. This study analyzed the occult HBV-genotypes in HCC patients. Methods To achieve our objective, matched serum and tissue samples were collected from 40 HCC patients. Three sets of primers were used for the HBV-DNA detection by nested-PCR, which cover the HBV-genome; Core, Surface and X genes. Genotyping system based on PCR using type-specific primers was applied on HBV-DNA positive samples. Results Intrahepatic occult HBV-DNA was detected in 62.5%, whereas; Serum occult HBV-DNA were detected in only 22.5% of HCC patients. In patients' positive for both anti-HBs and anti-HBc, 10% had occult HBV in serum. In serologically negative HCV patients, 63% had intrahepatic HBV-DNA, and 21% had HBV-DNA in serum samples. HBV-genotype D (32% and B (24% attributed predominantly to intrahepatic HBV infections in HCC patients, whereas HBV-genotype A (4% and C (8% infections were the least observed. Conclusion This is the first study to show the genotypes of occult HBV infection in HCC Patients.