WT1-AS promotes cell apoptosis in hepatocellular carcinoma through down-regulating of WT1.

Long Lv,Jianping Zhou,Gong Chen,Jun Li,Jianping Gong

doi:10.1186/s13046-015-0233-7

Abstract

BackgroundThe antisense of the tumor suppressor gene WT1 (WT1-AS) is a long non-coding RNA. The role of WT1-AS in the development of hepatocellular carcinoma (HCC) has not yet been elucidated.MethodsQuantitative real-time PCR and western blot analyses were used to measure levels of WT1-AS and its related genes in tumor and corresponding adjacent tumor tissues of HCC patients. The effect on HCC cell proliferation and apoptosis was assessed by EdU incorporation assays and PI-Annexin-V staining, respectively. ShRNA and dual-luciferase assays were used to investigate the regulatory relationship between WT1-AS and WT1 in cell lines.ResultsWT1-AS expression correlated negatively with WT1 expression in HCC tumor tissue. Kaplan-Meier curve analysis revealed that WT1-AS expression is a reliable indicator of HCC prognosis. The downregulation of WT1 expression by WT1-AS promoted cell apoptosis by suppressing the JAK/STAT3 signaling pathway. Bioinformatics analysis showed that WT1-AS downregulates WT1 by binding to the TATA region of the WT1 promotor. WT1-AS was also able to reverse WT1-mediated resistance to Dox based chemotherapy in HCC cells.ConclusionsWT1-AS downregulates WT1 expression in HCC tumors and promotes apoptosis by binding to the promoter region of WT1. Our findings suggest that WT1-AS may function as a tumor suppressor in HCC by reversing the oncogenic effects of WT1.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0233-7) contains supplementary material, which is available to authorized users.

Highlights

Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor and is the third leading cause of cancer-related death worldwide [1]
Wilms’ tumor 1 gene (WT1)-AS expression correlated negatively with WT1 expression in hepatocellular carcinoma (HCC) tumors In order to investigate whether changes in WT1-AS expression are associated with HCC, we quantified the expression of WT1-AS in tumor tissues and the corresponding adjacent tissues
WT1-AS expression was significantly reduced in tumor tissue compared to normal tissues (Fig. 1a), indicating that WT1-AS is involved in HCC

Summary

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor and is the third leading cause of cancer-related death worldwide [1]. There are several approaches to treating HCC, including surgical resection, liver transplantation, transcatheter arterial chemoembolization and local radiofrequency ablation, but none have improved the overall long-term survival of patients. This is largely attributed to the high malignancy and efficient intrahepatic invasion of HCC tumors, which leads to frequent reoccurrence after treatment [2, 3]. The long non-coding RNAs (lncRNAs) are important for predicting survival and metastasis in liver cancer [12]. The role of WT1-AS in the development of hepatocellular carcinoma (HCC) has not yet been elucidated

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Conclusion