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Wang Z.,Nanjing Medical University | Wang Z.,Jiangsu Provinces Key Medical Center for Hepatobiliary Surgery | Cao Y.,Nanjing Medical University | Cao Y.,Jiangsu Provinces Key Medical Center for Hepatobiliary Surgery | And 7 more authors.
PLoS ONE | Year: 2012

Background: Single nucleotide polymorphisms (SNPs) in microRNA-coding genes may participate in the process of carcinogenesis by altering the expression of tumor-related microRNAs. It has been suggested that two common SNPs rs2910164 in miR-146a and rs11614913 in miR-196a2 are associated with susceptibility to hepatocellular carcinoma (HCC). However, published results are inconsistent and inconclusive. In the present study, we performed a meta-analysis to systematically summarize the possible association between the two SNPs and the risk for HCC. Methodology/Principal Findings: We conducted a search of case-control studies on the associations of SNPs rs2910164 and/or rs11614913 with susceptibility to HCC in PubMed, EMBASE, ISI Web of Science, Cochrane Central Register of Controlled Trials, ScienceDirect, Wiley Online Library and Chinese National Knowledge Infrastructure databases. Data from eligible studies were extracted for meta-analysis. HCC risk associated with the two polymorphisms was estimated by pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). 5 studies on rs2910164 and 4 studies on rs11614913 were included in our meta-analysis. Our results showed that neither allele frequency nor genotype distribution of the two polymorphisms was associated with risk for HCC in all genetic models. Similarly, subgroup analysis in Chinese population showed no association between the two SNPs and the susceptibility to HCC. Conclusions/Significance: This meta-analysis suggests that two common SNPs rs2910164 and rs11614913 are not associated with the risk of HCC. Well-designed studies with larger sample size and more ethnic groups are required to further validate the results. © 2012 Wang et al.


Chen W.,Nanjing Medical University | Chen W.,Jiangsu Provinces Key Medical Center for Hepatobiliary Surgery | Wu J.,Nanjing University | Shi H.,Nanjing University | And 10 more authors.
BioMed Research International | Year: 2014

Purpose. Tumor microenvironment confers drug resistance to kinase inhibitors by increasing RKT ligand levels that result in the activation of cell-survival signaling including PI3K and MAPK signals. We assessed whether HSC-LX2 coculture conferred sorafenib resistance in Huh7 and revealed the mechanism underlying the drug resistance. Experimental Design. The effect of LX2 on sorafenib resistance was determined by coculture system with Huh7 cells. The rescue function of LX2 supernatants was assessed by MTT assay and fluorescence microscopy. The underlying mechanism was tested by administration of pathway inhibitors and manifested by Western blotting. Results. LX2 coculture significantly induced sorafenib resistance in Huh7 by activating p-Akt that led to reactivation of p-ERK. LX2 secreted HGF into the culture medium that triggered drug resistance, and exogenous HGF could also induce sorafenib resistance. The inhibition of p-Akt blocked sorafenib resistance caused by LX2 coculture. Increased phosphorylation of Jak2 and Stat3 was also detected in LX2 cocultured Huh7 cells. The Jak inhibitor tofacitinib reversed sorafenib resistance by blocking Jak2 and Stat3 activation. The combined administration of sorafenib and p-Stat3 inhibitor S3I-201 augmented induced apoptosis even in the presence of sorafenib resistance. Conclusions. HSC-LX2 coculture induced sorafenib resistance in Huh7 through multiple pathways: HGF/c-Met/Akt pathway and Jak2/Stat3 pathway. A combined administration of sorafenib and S3I-201 was able to augment sorafenib-induced apoptosis even in the presence of LX2 coculture. © 2014 Weibo Chen et al.


Chen W.,Nanjing Medical University | Chen W.,Jiangsu Provinces Key Medical Center for Hepatobiliary Surgery | Wang Z.,Nanjing Medical University | Wang Z.,Jiangsu Provinces Key Medical Center for Hepatobiliary Surgery | And 4 more authors.
Gastroenterology Research and Practice | Year: 2013

PP2A is a family of mammalian serine/threonine phosphatases that is involved in the control of many cellular functions including protein synthesis, cellular signaling, cell cycle determination, apoptosis, metabolism, and stress responses through the negative regulation of signaling pathways initiated by protein kinases. Rapid progress is being made in the understanding of PP2A complex and its functions. Emerging studies have correlated changes in PP2A with human diseases, especially cancer. PP2A is comprised of 3 subunits: a catalytic subunit, a scaffolding subunit, and a regulatory subunit. The alternations of the subunits have been shown to be in association with many human malignancies. Therapeutic agents targeting PP2A inhibitors or activating PP2A directly have shed light on the therapy of cancers. This review focuses on PP2A structure, cancer-associated mutations, and the targeting of PP2A-related molecules to restore or reactivate PP2A in anticancer therapy, especially in digestive system cancer therapy. © 2013 Weibo Chen et al.


Qu Z.,Nanjing University | Qu Z.,Jiangsu Provinces Key Medical Center For Hepatobiliary Surgery | Jiang C.,Nanjing University | Jiang C.,Jiangsu Provinces Key Medical Center For Hepatobiliary Surgery | And 4 more authors.
International Journal of Clinical and Experimental Medicine | Year: 2015

Exosomes are small membranous vesicles about 30~100 nm in diameter and formed from inward budding of the limiting membrane of multi-vesicular bodies (MVB). Exosomes are secreted by most cell types (including hepatocellular carcinoma cells) into the extracellular environment and can be isolated from various body fluids. Exosomes have broad biological function through delivering contained molecules to the target cells. Although limited studies on hepatocellular carcinoma (HCC) exosomes, increasing observations suggest that exosomes are important in HCC metastatic and prognosis, and exosomes are potential new molecular biomarkers for diagnosis and prognosis of HCC. In this review, we briefly summarize the latest findings on HCC exosomes, and their potential functions for novel diagnostic and therapeutic approaches of HCC. © 2015, E-Century Publishing Corporation. All rights Reserved.


Qu Z.,Nanjing University | Qu Z.,Jiangsu Provinces Key Medical Center for Hepatobiliary Surgery | Jiang C.,Nanjing University | Jiang C.,Jiangsu Provinces Key Medical Center for Hepatobiliary Surgery | And 3 more authors.
Molecular Medicine Reports | Year: 2016

Hepatocellular carcinoma (HCC) remains a disease with a high mortality rate, and the treatment for HCC remains limited. It is necessary to develop efficient and low toxicity drugs for the clinical treatment of HCC. Lenalidomide is a novel analogue of thalidomide and has anti-inflammatory, immunomodulatory and anti-angiogenic effects. The current study investigated the inhibitory effect against HCC cells of lenalidomide and thalidomide. The MTT assay was used to determine the cytotoxicity of lenalidomide and thalidomide, and morphological changes were observed by fluorescence microscopy. Caspase and VEGF protein expression were measured by ELISA analysis and western blotting. It was identified that treatment of cells with lenalidomide and thalidomide led to a dose-dependent inhibition of cell proliferation, and the two drugs were able to induce cells apoptosis and inhibit VEGF expression in HCC cells. In addition, lenalidomide was identified to exhibit greater effects than thalidomide at the same concentration. In conclusion, the results indicated that lenalidomide induces apoptosis and inhibits angiogenesis in HCC cells via caspase-3 and VEGF pathway, and these may provide a potential perspective for lenalidomide's application in clinical.


Qu Z.,Nanjing University | Qu Z.,Jiangsu Provinces Key Medical Center for Hepatobiliary Surgery | Wu J.,Nanjing University | Wu J.,Jiangsu Provinces Key Medical Center for Hepatobiliary Surgery | And 6 more authors.
Journal of Experimental and Clinical Cancer Research | Year: 2016

Background: Exosomes are carriers of intercellular information and regulate the tumor microenvironment. They play an important role in drug resistance by transporting RNA molecules and proteins. However, their effects on sorafenib resistance in hepatocellular carcinoma (HCC) are not completely understood. Methods: Exosomes were isolated from two invasive hepatoma cell lines (MHCC-97 L and MHCC-97H), and their roles in regulating sorafenib resistance in liver cancer cells as well as the underlying molecular mechanisms were determined. The exosomes were analyzed by TEM (transmission electron microscopy), DLS (dynamic light scattering) and Western blotting. Cell viability, cell death and the effects of exosomes on the HGF/c-Met/Akt signaling pathway in cancer cells were analyzed by MTT assays, FACS analysis and Western blotting, respectively. Moreover, the effects of exosomes on sorafenib resistance in vivo were investigated using a subcutaneous transplantation tumor model in athymic nude mice. Results: Exosomes derived from HCC cells were of the expected size and expressed the exosomal markers CD9 and CD63. They induced sorafenib resistance in vitro by activating the HGF/c-Met/Akt signaling pathway and inhibiting sorafenib-induced apoptosis. They also induced sorafenib resistance in vivo by inhibiting sorafenib-induced apoptosis. Moreover, exosomes derived from highly invasive tumor cells had greater efficacy than that of exosomes derived from less invasive cells. Conclusions: These data reveal the important role of HCC cell-derived exosomes in the drug resistance of liver cancer cells and demonstrate the intrinsic interaction between exosomes and their targeted tumor cells. This study suggests a new strategy for improving the effectiveness of sorafenib in treating HCC. © 2016 The Author(s).

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