Zhu Chuanying, Zhou Renhua, Zhou Qing, Chang Yuewen, Jiang Mawei
Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Orthopaedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Life Sci. 2016 Dec 1;166:34-40. doi: 10.1016/j.lfs.2016.10.002. Epub 2016 Oct 4.
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).
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.
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.
miR-539 functions as a tumor suppressor in HCC and reexpression of this miRNA offers a potential therapeutic strategy for this disease.
微小RNA（miRNA）失调在肿瘤生长和进展中起关键作用。在本研究中，我们试图探究miR - 539在肝细胞癌（HCC）中的表达及生物学作用。
检测miR - 539在人HCC组织和细胞系中的表达。确定miR - 539过表达对HCC细胞生长、致瘤性、三氧化二砷耐药性的影响。还研究了miR - 539在HCC中作用所涉及的信号通路。
相对于相应对照，miR - 539在HCC组织和细胞中表达下调。miR - 539过表达在体外抑制HCC细胞活力和集落形成，并在体内损害HCC细胞的致瘤性。用miR - 539模拟物转染显著诱导HepG2细胞凋亡，这与抗凋亡蛋白Bcl - 2和Bcl - xL表达降低以及Stat3磷酸化减少有关。Stat3组成型活性形式的过表达部分阻断了miR - 539介导的凋亡。miR - 539的强制表达使三氧化二砷耐药的HCC细胞对三氧化二砷重新敏感。与对照miRNA递送相比，瘤内递送miR - 539模拟物显著延缓了三氧化二砷耐药HCC细胞异种移植瘤的生长约3５％（P<0.05）。与三氧化二砷联合使用时，miR - 539模拟物使肿瘤负荷降低约80％。
miR - 539在HCC中起肿瘤抑制作用，该miRNA的重新表达为这种疾病提供了一种潜在的治疗策略。
