Chuanying Zhu1, Renhua Zhou1, Qing Zhou1, Yuewen Chang2, Mawei Jiang3. 1. Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China. 2. Department of Orthopaedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China. 3. Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: xiaojiangchengsun@163.com.
Abstract
AIMS: Dysregulation of microRNAs (miRNAs) plays a critical role in tumor growth and progression. In this study, we sought to explore the expression and biological roles of miR-539 in hepatocellular carcinoma (HCC). MAIN METHODS: The expression of miR-539 in human HCC tissues and cell lines was examined. The effects of miR-539 overexpression on cell growth, tumorigenicity, arsenic trioxide resistance of HCC cells were determined. The signaling pathways involved in the action of miR-539 in HCC were also investigated. KEY FINDINGS: miR-539 was downregulated in HCC tissues and cells, relative to corresponding controls. Overexpression of miR-539 inhibited HCC cell viability and colony formation in vitro and impaired tumorigenesis of HCC cells in vivo. Transfection with miR-539 mimic significantly induced apoptosis in HepG2 cells, which was coupled with reduced expression of anti-apoptotic proteins Bcl-2 and Bcl-xL and decreased phosphorylation of Stat3. Overexpression of a constitutively active form of Stat3 partially blocked miR-539-mediated apoptosis. Enforced expression of miR-539 resensitized arsenic trioxide-resistant HCC cells to arsenic trioxide. Intratumoral delivery of miR-539 mimic significantly retarded the growth of xenograft tumors from arsenic trioxide-resistant HCC cells by about 35%, compared to delivery of control miRNA (P<0.05). In combination with arsenic trioxide, miR-539 mimic yielded about 80% decrease in tumor burden. SIGNIFICANCE: miR-539 functions as a tumor suppressor in HCC and reexpression of this miRNA offers a potential therapeutic strategy for this disease.
AIMS: Dysregulation of microRNAs (miRNAs) plays a critical role in tumor growth and progression. In this study, we sought to explore the expression and biological roles of miR-539 in hepatocellular carcinoma (HCC). MAIN METHODS: The expression of miR-539 in human HCC tissues and cell lines was examined. The effects of miR-539 overexpression on cell growth, tumorigenicity, arsenic trioxide resistance of HCC cells were determined. The signaling pathways involved in the action of miR-539 in HCC were also investigated. KEY FINDINGS:miR-539 was downregulated in HCC tissues and cells, relative to corresponding controls. Overexpression of miR-539 inhibited HCC cell viability and colony formation in vitro and impaired tumorigenesis of HCC cells in vivo. Transfection with miR-539 mimic significantly induced apoptosis in HepG2 cells, which was coupled with reduced expression of anti-apoptotic proteins Bcl-2 and Bcl-xL and decreased phosphorylation of Stat3. Overexpression of a constitutively active form of Stat3 partially blocked miR-539-mediated apoptosis. Enforced expression of miR-539 resensitized arsenic trioxide-resistant HCC cells to arsenic trioxide. Intratumoral delivery of miR-539 mimic significantly retarded the growth of xenograft tumors from arsenic trioxide-resistant HCC cells by about 35%, compared to delivery of control miRNA (P<0.05). In combination with arsenic trioxide, miR-539 mimic yielded about 80% decrease in tumor burden. SIGNIFICANCE: miR-539 functions as a tumor suppressor in HCC and reexpression of this miRNA offers a potential therapeutic strategy for this disease.