Publications (77) View all
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Article: β-catenin/POU5F1/SOX2 transcription factor complex mediates IGF-1 receptor signaling and predicts poor prognosis in lung adenocarcinoma.
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ABSTRACT: Cancer stem-like cells (CSLCs) are crucial in tumor initiation and progression, however, the underlying mechanism for the self-renewal of cancer cells remains undefined. In the study, immunohistochemical analysis of specimens freshly excised from patients with lung adenocarcinoma (LAC) showed that high expression of insulin-like growth factor 1 receptor (IGF-1R) in LAC cells was positively correlated with the expressions of cancer stem cell markers, CD133 and ALDH1A1. IGF-1R activation enhanced POU5F1 expression on human lung adenocarcinoma stem-like cells (LACSLCs) through PI3K/AKT/GSK3β/β-catenin cascade. POU5F1 could form a novel complex with β-catenin and SOX2 to bind Nanog promoter for transcription to maintain self-renewal of LACSLCs, which was dependent on the functional IGF-1R. Genetic and pharmacological inhibition of IGF-1R abrogated LACSLC capabilities for self-renewal and tumorigenicity in vitro. In an in vivo xenograft tumor model, knockdown of either IGF-1R or POU5F1 impeded tumorigenic potentials of LACSLCs. By analyzing pathological specimens excised from 200 patients with lung adenocarcinoma, we found that co-localization of highly expressed IGF-1R with β-catenin and POU5F1 predicted poor prognosis. Taken together, we demonstrate that IGF-1R-mediated POU5F1 expression to form a complex with β-catenin and SOX2 is crucial for the self-renewal and oncogenic potentials of LACSLCs, and the integrative clinical detection of the expressions of IGF-1R, β-catenin and POU5F1 is indicatory for predicting prognosis in the patients of lung adenocarcinoma.Cancer Research 03/2013; · 7.86 Impact Factor -
Article: Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor -1alpha in hepatocellular carcinoma.
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ABSTRACT: BACKGROUND: High invasion and metastasis are the primary factors causing poor prognosis of patients with hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying these biological behaviors have not been completely elucidated. In this study, we investigate the molecular mechanism by which hypoxia promotes HCC invasion and metastasis through inducing epithelial-mesenchymal transition (EMT). METHODS: The expression of EMT markers was analyzed by immunohistochemistry. Effect of hypoxia on induction of EMT and ability of cell migration and invasion were performed. Luciferase reporter system was used for evaluation of Snail regulation by hypoxia-inducible factor -1alpha (HIF-1alpha). RESULTS: We found that overexpression of HIF-1alpha was observed in HCC liver tissues and was related to poor prognosis of HCC patients. HIF-1alpha expression profile was correlated with the expression levels of SNAI1, E-cadherin, N-cadherin and Vimentin. Hypoxia was able to induce EMT and enhance ability of invasion and migration in HCC cells. The same phenomena were also observed in CoCl2-treated cells. The shRNA-mediated HIF-1alpha suppression abrogated CoCl2-induced EMT and reduced ability of migration and invasion in HCC cells. Luciferase assay showed that HIF-1alpha transcriptional regulated the expression of SNAI1 based on two hypoxia response elements (HREs) in SNAI1 promoter. CONCLUSIONS: We demonstrated that hypoxia-stabilized HIF1alpha promoted EMT through increasing SNAI1 transcription in HCC cells. This data provided a potential therapeutic target for HCC treatment.BMC Cancer 03/2013; 13(1):108. · 3.01 Impact Factor -
Article: Oncolytic adenovirus co-expressing miRNA-34a and IL-24 induces superior antitumor activity in experimental tumor model.
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ABSTRACT: It has been demonstrated that numerous microRNAs (miRNAs) have potent tumor-suppressing effects on a variety of cancers, implicating a possible application of miRNA in tumor therapy. Oncolytic adenovirus is a suitable vector to deliver tumor suppressor genes for treatment of cancers. However, it remains unknown whether co-expression of tumor suppressor genes and miRNAs can contribute to a more potent antitumor capacity within an oncolytic adenovirus delivery system. In this study, we found that expression of miRNA-34a was reduced in hepatocellular carcinoma (HCC), and the reduced expression of miRNA-34a was associated with worse outcome of HCC patients. Thus, we developed an oncolytic adenoviral vector, AdCN205, to co-express miRNA-34a and IL-24 driven by an adenovirus endogenous E3 promoter in HCC cells. High levels of miRNA-34a and IL-24 expression were detected in AdCN205-IL-24-miR-34a-infected HCC cells. AdCN205-IL-24-miR-34a significantly induced dramatic antitumor activity, as compared with that induced by AdCN205-IL-24 or AdCN205-miR-34a alone. Transfer of miRNA-34a into HCC cells inhibited the expression of its target genes, Bcl-2 and SIRT1. Treatment of established xenograft HCC tumors with AdCN205-IL-24-miR-34a in a mouse model resulted in complete tumor regression without recurrence. Taken together, our data provide a promising and reasonable delivery strategy of double-aimed cancer therapy, in which miRNAs and tumor-suppressing genes are used simultaneously.Journal of Molecular Medicine 01/2013; · 4.67 Impact Factor -
Article: Decrease of 5-Hydroxymethylcytosine Is Associated with Progression of Hepatocellular Carcinoma through Downregulation of TET1.
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ABSTRACT: DNA methylation is an important epigenetic modification and is frequently altered in cancer. Convert of 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5 hmC) by ten-eleven translocation (TET) family enzymes plays important biological functions in embryonic stem cells, development, aging and disease. Recent reports showed that level of 5 hmC was altered in various types of cancers. However, the change of 5 hmC level in hepatocellular carcinoma (HCC) and association with clinical outcome were not well defined. Here, we reported that level of 5 hmC was decreased in HCC tissues, as compared with non-tumor tissues. Clincopathological analysis showed the decreased level of 5 hmC in HCC was associated with tumor size, AFP level and poor overall survival. We also found that the decreased level of 5 hmC in non-tumor tissues was associated with tumor recurrence in the first year after surgical resection. In an animal model with carcinogen DEN-induced HCC, we found that the level of 5 hmC was gradually decreased in the livers during the period of induction. There was further reduction of 5 hmC in tumor tissues when tumors were developed. In contrast, level of 5 mC was increased in HCC tissues and the increased 5 mC level was associated with capsular invasion, vascular thrombosis, tumor recurrence and overall survival. Furthermore, our data showed that expression of TET1, but not TET2 and TET3, was downregulated in HCC. Taken together, our data indicated 5 hmC may be served as a prognostic marker for HCC and the decreased expression of TET1 is likely one of the mechanisms underlying 5 hmC loss in HCC.PLoS ONE 01/2013; 8(5):e62828. · 4.09 Impact Factor -
Article: Does Hepatic Ischemia-Reperfusion Injury Induced by Hepatic Pedicle Clamping Affect Survival after Partial Hepatectomy for Hepatocellular Carcinoma?
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ABSTRACT: BACKGROUND: Liver resection offers a chance of cure for patients with hepatocellular carcinoma (HCC). Hepatic pedicle clamping (HPC) is commonly used to reduce blood loss during hepatectomy. Hepatic ischemia-reperfusion (I/R) injury has recently been reported to be a major factor in accelerated tumor growth. We therefore evaluated the effect of intermittent HPC on the prognosis of patients after liver resection. METHODS: The clinicopathological features and serum/tissue samples of 386 HCC patients who underwent curative liver resection were prospectively collected. The patients were divided into the HPC group (over 30 min) and the non-HPC group. Disease-free survival and overall survival were analyzed using multivariate analyses, Kaplan-Meier curves, and log-rank tests. Matrix metalloproteinases and E-selectin were measured to study hepatic I/R injury. RESULTS: The preoperative clinicopathological data were comparable between the HPC group (n = 224) and the non-HPC group (n = 162). During the study period, 257 of the 386 patients (66.6 %) developed tumor recurrence. The overall tumor recurrence and intrahepatic tumor recurrence rates were not significantly different between the two groups. There were no significant differences between the two groups with respect to the 1-, 3-, and 5-year disease-free and overall survival rates. Similarly, subgroup analyses also showed no marked difference in survival rates for patients with cirrhosis in the two groups. The levels of mRNA in liver tissues and serum concentrations of MMP-2, MMP-9, and E-selectin showed no significant differences between the pre- and post-occlusion periods. CONCLUSIONS: Intermittent HPC produced no adverse effect on disease-free and overall survival for patients who underwent liver resection for HCC.World Journal of Surgery 09/2012; · 2.36 Impact Factor
