Fangyu Zhao

Publications (8)50.39 Total impact

• Article: G Protein-Coupled Receptor 87 (GPR87) Promotes the Growth and Metastasis of CD133(+) Cancer Stem-Like Cells in Hepatocellular Carcinoma.

  Mingxia Yan, Hong Li, Miaoxin Zhu, Fangyu Zhao, Lixing Zhang, Taoyang Chen, Guoping Jiang, Haiyang Xie, Ying Cui, Ming Yao, Jinjun Li
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  ABSTRACT: Hepatocellular carcinoma (HCC) is a prevalent disease worldwide, and the majority of HCC-related deaths occur due to local invasion and distant metastasis. Cancer stem cells (CSCs) are a small subpopulation of cancer cells that have been hypothesized to be responsible for metastatic disease. Recently, we and others have identified a CSC population from human HCC cell lines and xenograft tumors characterized by their expression of CD133. However, the precise molecular mechanisms by which CD133(+) cancer stem-like cells mediate HCC metastasis have not been sufficiently analyzed. Here, we have sorted HCC cells using CD133 as a cancer stem cell (CSC) marker by magnetic-activated cell sorting (MACS) and demonstrated that the CD133(+) HCC cells not only possess greater migratory and invasive capacity in vitro but are also endowed with enhanced metastatic capacity in vivo and in human HCC specimens when compared to CD133(-) HCC cells. Gene expression analysis of the CD133(+) and CD133(-) cells of the HCC line SMMC-7721 revealed that G protein-coupled receptor 87 (GPR87) is highly expressed in CD133(+) HCC cells. In this study, we explored the role of GPR87 in the regulation of CD133 expression. We demonstrated that the overexpression of GPR87 up-regulated CD133 expression, promoted CSC-associated migratory and invasive properties in vitro, and increased tumor initiation in vivo. Conversely, silencing of GPR87 expression reduced the levels of CD133 expression. CONCLUSION: GPR87 promotes the growth and metastasis of CD133(+) cancer stem-like cells, and our findings may reveal new targets for HCC prevention or therapy.
  PLoS ONE 01/2013; 8(4):e61056. · 4.09 Impact Factor
• Article: BMP4 administration induces differentiation of CD133+ hepatic cancer stem cells, blocking their contributions to hepatocellular carcinoma.

  Lixing Zhang, Hefen Sun, Fangyu Zhao, Ping Lu, Chao Ge, Hong Li, Helei Hou, Mingxia Yan, Taoyang Chen, Guoping Jiang, Haiyang Xie, Ying Cui, Xiaowu Huang, Jia Fan, Ming Yao, Jinjun Li
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  ABSTRACT: CD133+ cancer stem cells (CSC) contribute to hepatocellular carcinoma (HCC) progression and resistance to therapy. Bone morphogenetic protein BMP4 plays an important role in hepatogenesis and hepatic stem cell differentiation, but little is known about its function in hepatic CSCs. In this study, we showed that high-dose exogenous BMP4 promotes CD133+ HCC CSC differentiation and inhibits the self-renewal, chemotherapeutic resistance, and tumorigenic capacity of these cells. Interestingly, we found that low-dose exogenous BMP4 upregulated CD133 protein expression in vitro, and endogenous BMP4 was preferentially expressed in CD133+ HCC CSCs, suggesting that low doses of BMP4 may facilitate CSC maintenance. A reduction in endogenous BMP4 levels decreased CD133 protein expression in vitro. In HCC tissues, expression of the BMP4 signaling target gene SMAD6 was positively correlated with CD133 expression. Activation of the Erk1/2 signaling pathway led to BMP4-mediated reduction in CD133 expression, which was reversed by treatment with MEK inhibitors. Taken together, our findings indicated that BMP4 might be a potent therapeutic agent in HCC that targets CSCs.
  Cancer Research 07/2012; 72(16):4276-85. · 7.86 Impact Factor
• Article: Isocorydine Targets the Drug-Resistant Cellular Side Population through PDCD4-Related Apoptosis in Hepatocellular Carcinoma.

  Ping Lu, Hefen Sun, Lixing Zhang, Helei Hou, Lin Zhang, Fangyu Zhao, Chao Ge, Ming Yao, Tingpu Wang, Jinjun Li
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  ABSTRACT: Isocorydine (ICD), an anticancer agent under current evaluation, decreased the percentage of side population (SP) cells significantly in hepatocellular carcinoma (HCC) cell lines. ICD treatment sensitized cancer cells to doxorubicin (DXR), a conventional clinical chemotherapeutic drug for HCC. We found that ICD decreased the percentage of SP cells in HCC cell lines by preferentially killing SP cells. In the early stage of treatment, ICD inhibited SP cell growth by arresting cells in G2/M; later, it induced apoptosis. Our xenograft model confirmed that ICD selectively reduced the size and weight of SP-induced tumor masses in vivo. Furthermore, it was found that programmed cell death 4 (PDCD4), a tumor suppressor gene, was relatively low when expressed in SP cells compared with non-SP cells, and its expression level was remarkably elevated when cells were treated with ICD. Taken together, these data suggest that ICD is a drug that may target the SP cells of HCC.
  Molecular Medicine 06/2012; 18(1):1136-46. · 3.76 Impact Factor
• Source

  Available from: Lixing Zhang

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

  Hefen Sun, Helei Hou, Ping Lu, Lixing Zhang, Fangyu Zhao, Chao Ge, Tingpu Wang, Ming Yao, Jinjun Li
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  ABSTRACT: 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.
  PLoS ONE 01/2012; 7(5):e36808. · 4.09 Impact Factor
• Article: Disruption of xCT inhibits cell growth via the ROS/autophagy pathway in hepatocellular carcinoma.

  Weijie Guo, Yingjun Zhao, Zhenfeng Zhang, Ning Tan, Fangyu Zhao, Chao Ge, Linhui Liang, Deshui Jia, Taoyang Chen, Ming Yao, Jinjun Li, Xianghuo He
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  ABSTRACT: xCT, the functional subunit of the system x(c)(-) which plays an important role in maintaining intracellular glutathione (GSH) levels, is expressed in various malignant tumors. Here, we demonstrated that xCT expression is often elevated in HCC and is associated with poor prognosis in HCC patients; moreover, disruption of xCT suppressed HCC cell growth both in vitro and in vivo. xCT dysfunction has also been shown to increase intracellular reactive oxygen species (ROS) levels, thus in turn led to autophagic cell death of HCC cells. Taken together, these findings suggest that xCT may be a promising therapeutic target for human HCC.
  Cancer letters 08/2011; 312(1):55-61. · 4.86 Impact Factor
• Source

  Available from: Deshui Jia

  Article: Genome-wide copy number analyses identified novel cancer genes in hepatocellular carcinoma.

  Deshui Jia, Lin Wei, Weijie Guo, Ruopeng Zha, Meiyan Bao, Zhiao Chen, Yingjun Zhao, Chao Ge, Fangyu Zhao, Taoyang Chen, Ming Yao, Jinjun Li, Hongyang Wang, Jianren Gu, Xianghuo He
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  ABSTRACT: A powerful way to identify driver genes with causal roles in carcinogenesis is to detect genomic regions that undergo frequent alterations in cancers. Here we identified 1,241 regions of somatic copy number alterations in 58 paired hepatocellular carcinoma (HCC) tumors and adjacent nontumor tissues using genome-wide single nucleotide polymorphism (SNP) 6.0 arrays. Subsequently, by integrating copy number profiles with gene expression signatures derived from the same HCC patients, we identified 362 differentially expressed genes within the aberrant regions. Among these, 20 candidate genes were chosen for further functional assessments. One novel tumor suppressor (tripartite motif-containing 35 [TRIM35]) and two putative oncogenes (hairy/enhancer-of-split related with YRPW motif 1 [HEY1] and small nuclear ribonucleoprotein polypeptide E [SNRPE]) were discovered by various in vitro and in vivo tumorigenicity experiments. Importantly, it was demonstrated that decreases of TRIM35 expression are a frequent event in HCC and the expression level of TRIM35 was negatively correlated with tumor size, histological grade, and serum alpha-fetoprotein concentration. CONCLUSION: These results showed that integration of genomic and transcriptional data offers powerful potential for identifying novel cancer genes in HCC pathogenesis.
  Hepatology 06/2011; 54(4):1227-36. · 11.66 Impact Factor
• Article: Hypoxia-inducible factor 1 alpha-activated angiopoietin-like protein 4 contributes to tumor metastasis via vascular cell adhesion molecule-1/integrin β1 signaling in human hepatocellular carcinoma.

  Hong Li, Chao Ge, Fangyu Zhao, Mingxia Yan, Chen Hu, Deshui Jia, Hua Tian, Miaoxin Zhu, Taoyang Chen, Guoping Jiang, Haiyang Xie, Ying Cui, Jianren Gu, Hong Tu, Xianghuo He, Ming Yao, Yongzhong Liu, Jinjun Li
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  ABSTRACT: Angiopoietin-like protein 4 (ANGPTL4) plays complex and often contradictory roles in vascular biology and tumor metastasis, but little is known about its function in hepatocellular carcinoma (HCC) metastasis. In the present study, we showed that hypoxia-inducible factor 1α (HIF-1α) directly up-regulates ANGPTL4, and its stableness positively correlates with ANGPTL4 expression in HCC tissue. Overexpression of ANGPTL4 significantly increased HCC cell transendothelial migration in vitro and intrahepatic and distal pulmonary metastasis in vivo, whereas silencing ANGPTL4 expression or treatment with a neutralizing antibody specific for ANGPTL4 protein resulted in a reduced transendothelial migration. We also found that serum ANGPTL4 is higher in HCC patients, compared to healthy control, and correlates with intrahepatic metastasis and histological grade. Further, secreted ANGPTL4 promotes transendothelial migration and metastasis of HCC cells in vitro and in vivo through the up-regulation of vascular cell adhesion molecule-1 (VCAM-1) of human umbilical vein endothelial cells and the activation of the VCAM-1/integrin β1 axis. Conclusion: ANGPTL4 is a target gene of HIF-1α and acts as an important regulator in the metastasis of HCC. Serum ANGPTL4 correlates with tumor progression and metastasis and might be used to indicate prognosis in HCC patients.
  Hepatology 06/2011; 54(3):910-9. · 11.66 Impact Factor
• Article: TC21 promotes cell motility and metastasis by regulating the expression of E-cadherin and N-cadherin in hepatocellular carcinoma.

  Hairong Luo, Xiangfang Hao, Chao Ge, Fangyu Zhao, Miaoxin Zhu, Taoyang Chen, Ming Yao, Xianghuo He, Jinjun Li
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  ABSTRACT: Hepatocellular carcinoma (HCC) is an aggressive type of cancer, and it may be at an advanced stage when it is detected. It has been shown that TC21, a member of the Ras superfamily, is associated with the proliferation, migration and transformation of tumor cells. Previous studies have shown that TC21 is overexpressed in breast, esophageal and oral carcinomas, and that it is closely associated with the early stages of tumorigenesis. In this study, we demonstrate that TC21 overexpression promotes the motility of HCC cells in vitro and intrahepatic metastasis in vivo. Furthermore, experiments examining the effects of both the ectopic expression of TC21 and siRNA treatment in HCC cells showed that TC21 alters the expression of the adhesive molecules E-cadherin and N-cadherin. Our data suggest that TC21 is associated with tumor progression and poor prognosis in HCC.
  International Journal of Oncology 10/2010; 37(4):853-9. · 2.40 Impact Factor