Eastern Hepatobiliary Surgery Institute

Shanghai, China

Eastern Hepatobiliary Surgery Institute

Shanghai, China
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Cui X.,The International Cooperation Laboratory on Signal Transduction | Cui X.,Eastern Hepatobiliary Surgery Institute | Li X.,Eastern Hepatobiliary Surgery Institute | Li J.,Shanghai University | And 10 more authors.
Oncotarget | Year: 2017

Capturing the predominant driver genes is critical in the analysis of highthroughput experimental data; however, existing methods scarcely include the unique characters of biological networks. Herein we introduced a ranking-based computational framework (inFRank) to rank the proteins by their influence. Using inFRank, we identified the top 20 influential genes in hepatocellular carcinoma (HCC). Network analysis revealed a prominent community composed of 7 influential genes. Intriguingly, five genes among the community were critical for mitotic spindle assembly checkpoint (SAC), suggesting that dysregulation of SAC could be a distinct feature of HCC and targeting SAC-associated genes might be a promising therapeutic strategy. Cox regression analysis revealed that CDC20 exerted as an independent risk factor for patient survival, indicating that CDC20 could be a novel biomarker for HCC prognosis. inFRank was then used for pan-cancer study, and all of the most influential genes in 18 cancers were achieved. We identified altogether 19 genes that were important in multiple cancers, and observed that cancers originating from the same organ or function-related organs tended to share more influential genes. Collectively, our results demonstrated that the inFRank was a powerful approach for deep interpretation of high-throughput data and better understanding of complex diseases. © Cui et al.


Ning B.-F.,Shanghai Changzheng Hospital | Ding J.,Eastern Hepatobiliary Surgery Institute | Yin C.,Shanghai Changzheng Hospital | Zhong W.,Shanghai Changzheng Hospital | And 10 more authors.
Cancer Research | Year: 2010

Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor that plays a key role in hepatocyte differentiation and the maintenance of hepatic function, but its role in hepatocarcinogenesis has yet to be examined. Here, we report evidence of a suppressor role for HNF4α in liver cancer. HNF4α expression was progressively decreased in the diethylinitrosamine- induced rat model of liver carcinogenesis. In human liver tissues, HNF4α expression was decreased in cirrhotic tissue and further decreased in hepatocarcinoma relative to healthy tissue. Notably, an inverse correlation existed with epithelial-mesenchymal transition (EMT). Enforced expression of HNF4α attenuated hepatocyte EMT during hepatocarcinogenesis, alleviated hepatic fibrosis, and blocked hepatocellular carcinoma (HCC) occurrence. In parallel, stem cell marker gene expression was inhibited along with cancer stem/progenitor cell generation. Further, enforced expression of HNF4α inhibited activation of β-catenin, which is closely associated with EMT and hepatocarcinogenesis. Taken together, our results suggest that the inhibitory effect of HNF4α on HCC development might be attributed to suppression of hepatocyte EMT and cancer stem cell generation through an inhibition of β-catenin signaling pathways. More generally, our findings broaden knowledge on the biological significance of HNF4α in HCC development, and they imply novel strategies for HCC prevention through the manipulation of differentiation-determining transcription factors in various types of carcinomas. ©2010 AACR.


Zheng C.G.,The Second Military Medical University | Shi H.G.,The 401 Hospital of PLA | Tang G.S.,Second Military Medical University | Wang W.Y.,The Second Military Medical University | And 2 more authors.
American Journal of Translational Research | Year: 2015

Acetaminophen-induced liver injury represents the most frequent cause of drug-induced liver failure in the world. Portulaca oleracea L., a widely distributed weed, has been used as a folk medicine in many countries. Previously, we reported that the ethanol extracts of Portulaca oleracea L. (PO) exhibited significant anti-hypoxic activity. In the present study, we investigated the role of PO on acetaminophen (APAP) induced hepatotoxicity. The results demonstrated that PO was an effective anti-oxidative agent, which could, to some extent, reverse APAP-induced hepatotoxicity by regulating the reactive oxygen species (ROS) in the liver of mice. At the same time, PO treatment significantly decreased mice serum levels of IL-6 and TNFα and their mRNA expression in liver tissue IL-α and TNFα play an important role during APAP-induced liver injury. Furthermore, PO inhibited APAP and TNFα-induced activation of JNK, whose activation play an important effect during APAP induced liver injury. These findings sug-gested that administration of PO may be an effective strategy to prevent or treat liver injury induced by APAP. © 2015, E-Century Publishing Corporation. All right reserved.


Hu L.,Eastern Hepatobiliary Surgery Institute | Chen L.,Eastern Hepatobiliary Surgery Institute | Li L.,Eastern Hepatobiliary Surgery Institute | Sun H.,Eastern Hepatobiliary Surgery Institute | And 6 more authors.
Journal of Virology | Year: 2011

Hepatitis B virus X protein (HBx) is implicated in the pathogenesis of hepatitis B virus (HBV)-associated liver diseases. However, whether HBx has the ability to disturb the susceptibility of hepatocytes to common chemotherapeutic agents remains incompletely understood. Here we demonstrate that HBx enhances cisplatin-induced hepatotoxicity by a mechanism involving degradation of Mcl-1, an antiapoptotic member of the Bcl-2 family. Ectopic expression of HBx sensitized hepatocytes to cisplatin-induced apoptosis, which was accompanied by a marked downregulation of Mcl-1 but not of Bcl-2 or Bcl-xL. Overexpression of Mcl-1 prevented HBx-induced proapoptotic and proinflammatory effects during cisplatin treatment both in vitro and in vivo. HBx-induced dysregulation of Mcl-1 resulted mainly from posttranslational degradation rather than transcription repression. Moreover, a caspase-3 inhibitor effectively abrogated HBx-enhanced Mcl-1 degradation and cell death. Importantly, antioxidants blocked activation of caspase-3 and acceleration of Mcl-1 loss, as well as cell death, in HBx-expressing hepatocytes upon cisplatin exposure in vitro and in vivo. Collectively, these data implicate oxidative stress-dependent caspase-3-mediated degradation of Mcl-1 as a mechanism contributing to HBx-mediated sensitization of cisplatin-induced hepatotoxicity. A combination of cisplatin and antioxidants might provide more advantage than cisplatin alone in the treatment of cancer patients with chronic HBV infection. Copyright © 2011, American Society for Microbiology. All Rights Reserved.


Hou Y.,Tongren University | Zhou M.,Tongren University | Xie J.,Tongren University | Chao P.,Tongren University | And 2 more authors.
Breast Cancer: Targets and Therapy | Year: 2017

Hyperglycemia or diabetes mellitus (DM), which is characterized by high blood glucose levels, has been linked to an increased risk of cancer for years. However, the underlying molecular mechanisms of the pathophysiological link are not yet fully understood. In this study, we demonstrate that high glucose levels promote the proliferation of breast cancer cells by stimulating epidermal growth factor receptor (EGFR) activation and the Rho family GTPase Rac1 and Cdc42 mediate the corresponding signaling induced by high glucose levels. We further show that Cdc42 promotes EGFR phosphorylation by blocking EGFR degradation, which may be mediated by the Cbl proteins, whereas the Rac1-mediated EGFR phosphorylation is independent of EGFR degradation. Our findings elucidate a part of the underlying molecular mechanism of the link between high glucose levels and tumorigenesis in breast cancer and may provide new insights on the therapeutic strategy for cancer patients with diabetes or hyperglycemia. © 2017 Hou et al.


Feng Q.,Cornell University | Feng Q.,Eastern Hepatobiliary Surgery Institute | Zhang C.,Cornell University | Lum D.,University of Utah | And 6 more authors.
Nature Communications | Year: 2017

Non-classical secretory vesicles, collectively referred to as extracellular vesicles (EVs), have been implicated in different aspects of cancer cell survival and metastasis. Here, we describe how a specific class of EVs, called microvesicles (MVs), activates VEGF receptors and tumour angiogenesis through a unique 90 kDa form of VEGF (VEGF90K). We show that VEGF90K is generated by the crosslinking of VEGF 165, catalysed by the enzyme tissue transglutaminase, and associates with MVs through its interaction with the chaperone Hsp90. We further demonstrate that MV-associated VEGF90K has a weakened affinity for Bevacizumab, causing Bevacizumab to be ineffective in blocking MV-dependent VEGF receptor activation. However, treatment with an Hsp90 inhibitor releases VEGF90K from MVs, restoring the sensitivity of VEGF90K to Bevacizumab. These findings reveal a novel mechanism by which cancer cell-derived MVs influence the tumour microenvironment and highlight the importance of recognizing their unique properties when considering drug treatment strategies. © 2017 The Author(s).


Li R.,Fudan University | Yang Y.,Eastern Hepatobiliary Surgery Hospital | Yang Y.,Eastern Hepatobiliary Surgery Institute | An Y.,Fudan University | And 10 more authors.
Carcinogenesis | Year: 2011

Environmental risk factors cause DNA damages. Imprecise DNA repair leads to chromosome aberrations, genome destabilization and hepatocarcinogenesis. Ku is a key DNA double-strand break repair protein. We hypothesized that the genetic variants in Ku subunits encoding genes, XRCC5/XRCC6, may contribute to hepatocellular carcinoma (HCC) susceptibility. We genotyped 13 common single nucleotide polymorphisms (SNPs) in XRCC5 and XRCC6 and evaluated their associations with HCC risk in 689 pathologically confirmed cases and 690 cancer-free controls from a Chinese population. We found that a significantly reduced risk for HCC was associated with XRCC5 rs16855458 [odds ratio (OR) = 0.59; 95% confidence interval (CI) = 0.43-0.81; CA 1 AAversus CC] and a significantly increased risk for HCC was associated with XRCC5 rs9288516 (OR = 2.02; 95% CI = 1.42-2.86; TA 1 AA versus TT) even after Bonferroni correction (Pcorrected = 0.026 and 0.002, respectively). The effects of rs16855458 (OR = 0.57; 95% CI = 0.37-0.86, P = 0.008) and rs9288516 (OR = 1.86; 95% CI = 1.19-2.90, P = 0.007) were more significant in hepatitis B surface antigen-infected subjects than non-infected subjects. The haplotype-based analysis revealed that in XRCC5, AA in block 1 (OR = 0.63; 95% CI = 0.48-0.83) and CGGTT in block 2 (OR = 0.52; 95% CI = 0.39-0.69) were associated with decreased HCC risk (Pcorrected = 0.013 and <0.001, respectively). The aforementioned two SNPs exhibited a significant cumulative risk effect (Ptrend < 0.001). Additionally, potential interaction among XRCC5 rs9288516 and rs2267437, rs5751131 in XRCC6 was indicated by the multifactor dimensionality reduction analysis. In conclusion, XRCC5 variants may play a role in determining individual's HCC susceptibility, which warranted validation in larger studies. © The Author 2011. Published by Oxford University Press. All rights reserved.


PubMed | Eastern Hepatobiliary Surgery Institute
Type: Journal Article | Journal: Journal of virology | Year: 2011

Hepatitis B virus X protein (HBx) is implicated in the pathogenesis of hepatitis B virus (HBV)-associated liver diseases. However, whether HBx has the ability to disturb the susceptibility of hepatocytes to common chemotherapeutic agents remains incompletely understood. Here we demonstrate that HBx enhances cisplatin-induced hepatotoxicity by a mechanism involving degradation of Mcl-1, an antiapoptotic member of the Bcl-2 family. Ectopic expression of HBx sensitized hepatocytes to cisplatin-induced apoptosis, which was accompanied by a marked downregulation of Mcl-1 but not of Bcl-2 or Bcl-xL. Overexpression of Mcl-1 prevented HBx-induced proapoptotic and proinflammatory effects during cisplatin treatment both in vitro and in vivo. HBx-induced dysregulation of Mcl-1 resulted mainly from posttranslational degradation rather than transcription repression. Moreover, a caspase-3 inhibitor effectively abrogated HBx-enhanced Mcl-1 degradation and cell death. Importantly, antioxidants blocked activation of caspase-3 and acceleration of Mcl-1 loss, as well as cell death, in HBx-expressing hepatocytes upon cisplatin exposure in vitro and in vivo. Collectively, these data implicate oxidative stress-dependent caspase-3-mediated degradation of Mcl-1 as a mechanism contributing to HBx-mediated sensitization of cisplatin-induced hepatotoxicity. A combination of cisplatin and antioxidants might provide more advantage than cisplatin alone in the treatment of cancer patients with chronic HBV infection.

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