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Fenglin, China

Li Y.,Wuhan University | Tang Z.-Y.,Liver Cancer Institute | Hou J.-X.,Wuhan University
Nature Reviews Gastroenterology and Hepatology | Year: 2012

Hepatocellular carcinoma (HCC) ranks as the third most common cause of death from cancer worldwide. Although major risk factors for the development of HCC have been defined, many aspects of the evolution of hepatocellular carcinogenesis and metastasis are still unknown. Suitable animal models are, therefore, essential to promote our understanding of the molecular, cellular and pathophysiological mechanisms of HCC and for the development of new therapeutic strategies. This Review provides an overview of animal models that are relevant to HCC development, metastasis and treatment. For HCC development, this Review focuses on transgenic mouse models of HBV and HCV infection, which provide experimental evidence that viral genes could initiate or promote liver carcinogenesis. Animal models of HCC metastasis provide platforms to elucidate the mechanisms of HCC metastasis, to study the interaction between the microenvironment and HCC invasion and to conduct intervention studies. In addition, animal models have been developed to investigate the effects of new treatment modalities. The criteria for establishing ideal HCC animal models are also discussed. © 2011 Macmillan Publishers Limited. All rights reserved. Source


Tang Z.-Y.,Liver Cancer Institute
Nature Reviews Gastroenterology and Hepatology | Year: 2011

Owing to the shortage of donor organs, improved selection criteria are needed for allocating patients with hepatocellular carcinoma (HCC) to receive orthotopic liver transplantation (OLT). A study has found that the neutrophil:lymphocyte ratio independently predicts tumor recurrence after OLT for HCC and, therefore, might constitute a simple entry criterion that measures host inflammation status. Source


Ai J.,CAS Shanghai Institute of Materia Medica | Tang Q.,Ocean University of China | Wu Y.,Ocean University of China | Xu Y.,Liver Cancer Institute | And 19 more authors.
Journal of the National Cancer Institute | Year: 2011

Background Expression of the polymeric immunoglobulin receptor (pIgR), a transporter of polymeric IgA and IgM, is commonly increased in response to viral or bacterial infections, linking innate and adaptive immunity. Abnormal expression of pIgR in cancer was also observed, but its clinical relevance remains uncertain. Methods A human hepatocellular carcinoma (HCC) tissue microarray (n = 254) was used to investigate the association between pIgR expression and early recurrence. An experimental lung metastasis model using severe combined immune-deficient mice was applied to determine the metastatic potential of Madin-Darby canine kidney (n = 5 mice per group) and SMMC-7721 (n = 12 mice per group) cells overexpressing pIgR vs control cells. RNA interference, immunoprecipitation, and immunoblotting were performed to investigate the potential role for pIgR in the induction of epithelial- mesenchymal transition (EMT). In vitro studies (co-immunoprecipitation, immunoblotting, and migration, invasion, and adhesion assays) were used to determine the mechanisms behind pIgR-mediated metastasis. All statistical tests were two-sided. Results High expression of pIgR was statistically significantly associated with early recurrence in early-stage HCC and in hepatitis B surface antigen-positive HCC patients (log-rank P =. 02). Mice injected with pIgR-overexpressing cells had a statistically significantly higher number of lung metastases compared with respective control cells (Madin-Darby canine kidney cells: pIgR mean = 29.4 metastatic nodules per lung vs control mean = 0.0 metastatic nodules per lung, difference = 29.4 metastatic nodules per lung, 95% confidence interval = 13.0 to 45.8, P =. 001; SMMC-7721 cells: pIgR mean = 10.4 metastatic nodules per lung vs control mean = 2.2 metastatic nodules per lung, difference = 8.2 metastatic nodules per lung, 95% confidence interval = 1.0 to 15.5, P =. 03). Furthermore, high expression of pIgR was sufficient to induce EMT through activation of Smad signaling. Conclusions pIgR plays a role in the induction of EMT. Our results identify pIgR as a potential link between hepatitis B virus-derived hepatitis and HCC metastasis and provide evidence in support of pIgR as a prognostic biomarker for HCC and a potential therapeutic target. © 2011 The Author. Source


Yu X.,Central South University | Deng Q.,Central South University | Li W.,Central South University | Xiao L.,Central South University | And 12 more authors.
Oncotarget | Year: 2015

Necroptosis/regulated necrosis is a caspase-independent, but receptor interacting protein kinase (RIPK)-dependent form of cell death. In previous studies, neoalbaconol (NA), a constituent extracted from Albatrellus confluens, was demonstrated to induce necroptosis in some cancer cell lines. The molecular mechanism of NA-induced necroptosis is described in this research study. We determined that NA-induced cell death is partly dependent on tumor necrosis factor a (TNFα) feed-forward signaling. More importantly, NA abolished the ubiquitination of RIPK1 by down-regulating E3 ubiquitin ligases, cellular inhibitors of apoptosis protein 1/2 (cIAP1/2) and TNFα receptor-associated factors (TRAFs). The suppression of RIPK1 ubiquitination induced the activation of the non-canonical nuclear factor-κB (NF-κB) pathway and stimulated the transcription of TNFα. Moreover, we also found that NA caused RIPK3-mediated reactive oxygen species (ROS) production and contribution to cell death. Taken together, these results suggested that two distinct mechanisms are involved in NA-induced necroptosis and include RIPK1/NF-κB-dependent expression of TNFα and RIPK3-dependent generation of ROS. Source


Shi Y.-H.,Liver Cancer Institute | Ding Z.-B.,Liver Cancer Institute | Zhou J.,Liver Cancer Institute | Zhou J.,Fudan University | And 10 more authors.
Autophagy | Year: 2011

Sorafenib, a potent multikinase inhibitor, has been recognized as the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). However, the direct functional mechanism of tumor lethality mediated by sorafenib remains to be fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, we showed sorafenib induced both apoptosis and autophagy in human HCC cells through a mechanism that involved endoplasmic reticulum (ER) stress and was independent of the MEK1/2-ERK1/2 pathway. Upregulation of IRE1 signals from sorafenib-induced ER stress was critical for the induction of autophagy. Moreover, autophagy activation alleviated the ER stress-induced cell death. Inhibition of autophagy using either pharmacological inhibitors or essential autophagy gene knockdown enhanced cell death in sorafenib treated HCC cell lines. Critically, the combination of sorafenib with the autophagy inhibitor chloroquine produced more pronounced tumor suppression in HCC both in vivo and in vitro. These findings indicated that both ER stress and autophagy were involved in the cell death evoked by sorafenib in HCC cells. The combination of autophagy modulation and molecular targeted therapy is a promising therapeutic strategy in treatment of HCC. © 2011 Landes Bioscience. Source

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