National Center for Liver Cancer Research

Shanghai, China

National Center for Liver Cancer Research

Shanghai, China

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Fang T.,University for International Cooperation | Lv H.,University for International Cooperation | Wu F.,University for International Cooperation | Wang C.,University for International Cooperation | And 18 more authors.
Cancer Letters | Year: 2017

Accumulating evidence suggests that cancer stem cells (CSCs), a small subset of cancer cells, are responsible for tumor initiation, progression, relapse and metastasis. Musashi 2 (MSI2), a RNA-binding protein, was proposed to be a potent oncogene playing key roles in myeloid leukemia and gastrointestinal malignancies. However, it remains elusive how MSI2 regulates stem cell features in HCC. Herein, we demonstrated that MSI2 was highly expressed in liver CSCs. Overexpression or knockdown of MSI2 altered CSC-related gene expression, self-renewal as well as resistance to chemotherapy in HCC cell lines. In mouse xenograft models, MSI2 could markedly enhance tumorigenicity. Mechanistically, overexpression of MSI2 resulted in the upregulation of Lin28A. Stemness and chemotherapeutic drug resistance induced by MSI2 overexpression were dramatically reduced by Lin28A knockdown. Moreover, MSI2 and LIN28A levels positively correlated with the clinical severity and prognosis in HCC patients. In conclusion, MSI2 might play a crucial role in sustaining stemness and chemoresistance of liver CSCs via LIN28A-dependent manner in HCC. Our findings revealed that MSI2 and Lin28A might be used as potential therapeutic targets for eradicating liver CSCs. © 2016

Wang M.-D.,University for International Cooperation | Wang M.-D.,National Center for Liver Cancer Research | Wu H.,University for International Cooperation | Huang S.,University for International Cooperation | And 30 more authors.
Oncotarget | Year: 2016

Due to a high rate of nutrient consumption and inadequate vascularization, hepatocellular carcinoma (HCC) cells constantly undergo metabolic stress during tumor development. Hepatitis B virus (HBV) X protein (HBx) has been implicated in the pathogenesis of HBV-induced HCC. In this study, we investigated the functional roles of HBx in HCC adaptation to metabolic stress. Up-regulation of HBx increased the intracellular ATP and NADPH generation, and induced the resistance to glucose deprivation, whereas depletion of HBx via siRNA abolished these effects and conferred HCC cells sensitive to glucose restriction. Though HBx did not affect the glycolysis and oxidative phosphorylation capacity of HCC cells under normal culture conditions, it facilitated fatty acid oxidation (FAO) in the absence of glucose, which maintained NADPH and ATP levels. Further investigation showed that HBx expression, under glucose deprivation, stimulated phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) via a calcium/CaMKK-dependent pathway, which was required for the activation of FAO. Conversely, inhibition of FAO by etomoxir (ETO) restored the sensitivity of HBx-expressing cells to glucose deficiency in vitro and retarded xenograft tumor formation in vivo. Finally, HBx-induced activation of the AMPK and FAO pathways were also observed in xenograft tumors and HBV-associated HCC specimens. Our data suggest that HBx plays a key role in the maintenance of redox and energy homeostasis by activating FAO, which is critical for HCC cell survival under conditions of metabolic stress and might be exploited for therapeutic benefit.

Zheng L.,Eastern Hepatobiliary Surgery Institute Hospital | Zheng L.,Shanghai University | Zheng L.,National Center for Liver Cancer Research | Yang W.,Eastern Hepatobiliary Surgery Institute Hospital | And 23 more authors.
Clinical Cancer Research | Year: 2013

Purpose: The AMP-activated protein kinase (AMPK) serves as an energy sensor in eukaryotic cells and occupies a central role in linking metabolism and cancer development. However, the phosphorylation status of AMPK and its therapeutic value in human hepatocellular carcinoma (HCC) remain unclear. Experimental Design: The phosphorylation status of AMPK (Thr172) was determined by immunoblotting and immunostaining in specimens from 273 patients with HCC (including 253 patients with hepatitis B virus -related HCC). Kaplan-Meier survival analysis was used to determine the correlation with prognosis. The effects of therapeutic metformin/AMPK activation were assessed in cultured human HCC cell lines and primary HCC cells in vitro and in xenograft tumors model in vivo. To define the mechanisms of anticancer effects of metformin, we examined its influence on AMPK activation and NF-kB pathway. Results: AMPK is dysfunctional in patients with HCC, and low p-AMPK staining is correlated with aggressive clinicopathologic features and poor prognosis. Activation of AMPK by metformin not only inhibited HCC cells growth in vitro and in vivo, but also augmented cisplatin-induced growth inhibition in HCC cells. Knockdown of AMPKa expression can greatly decrease the inhibitory effect of metformin, indicating that AMPK activation is required for the anticancer action of metformin. Mechanistically, metformin/AMPK activation inhibited NF-kB signaling through upregulation of IkBa. Activation of NFkB signaling by ectopic expression of P65 or overexpression of an undegradable mutant form of IkBa attenuated the anticancer effects of metformin. Conclusions: These results present novel insight into a critical role of AMPK in HCC progression. Anticancer effects of therapeutic metformin/AMPK activation unravel metformin?s potential in treatment of HCC. © 2013 American Association for Cancer Research.

Zou S.-S.,Eastern Hepatobiliary Surgery Institute Hospital | Zou S.-S.,National Center for Liver Cancer Research | Yang W.,Eastern Hepatobiliary Surgery Institute Hospital | Yang W.,National Center for Liver Cancer Research | And 27 more authors.
Cancer Letters | Year: 2013

β-Catenin plays many critical roles during various liver physiological and pathological processes. However, the role of β-Catenin in acute liver failure remains unclear. Using hepatocyte specific β-Catenin knockout mice, we found that loss of β-Catenin in hepatocyte significantly reduced GalN/LPS-induced liver damage and hepatocyte apoptosis, but exacerbated Jo2-mediated liver injury. Mechanistically, the dual effects of β-Catenin attributes on its function of inhibiting NF-κB signaling, which aggravates oxidative stress but decreases Fas expression under injury conditions. In conclusion, β-Catenin plays an important role in regulating the balance between TNF-α and Fas-induced liver injury via its effect on NF-κB. © 2013 Elsevier Ireland Ltd.

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