MicroRNA miR-495 regulates the development of Hepatocellular Carcinoma by targeting C1q/tumor necrosis factor-related protein-3 (CTRP3)

Hepatocellular carcinoma (HCC) represents a type of lethal cancer in the world and its treatment options produce limited and unsatisfactory effectiveness. MicroRNAs (miRNAs) that play critical roles in tumorigenesis have shown promising clinical therapeutic potential. Here, we reported that miRNA-495 (miR-495) plays important roles in inhibiting HCC cell growth via its regulation of cell-cycle progression as well as senescence. MiR-495 showed low levels in human HCC tissues and cells. Overexpressing miR-495 in HCC cells caused strong cell growth inhibition, which results from cell-cycle arrest and senescence. CTRP3 functioned as a possible target of miR-495 in HCC cells by bioinformatics prediction and biological assay. By inhibiting the expression of CTRP3 with siRNA, HCC cells also showed similar growth inhibition as miR-495 overexpression. The re-expression of CTRP3 in HCC cells with high-level miR-495 abolished miR-495 and caused cell growth inhibition. These results strongly suggested that CTRP3 was the functional target that weakened the effects of miR-495 in HCC cells. The in vivo experiment demonstrated miR-495 overexpression had great therapeutic effects on HCC in xenograft. Above all, this research revealed that miR-495 is essential in suppressing HCC growth, and its application serves as a promising strategy for HCC treatment.

肝细胞癌（Hepatocellular carcinoma, HCC）是全球范围内致死性恶性肿瘤之一，现有治疗方案的疗效有限且不尽如人意。微小RNA（MicroRNAs, miRNAs）在肿瘤发生进程中发挥关键调控作用，展现出颇具前景的临床治疗潜力。本研究证实，微小RNA-495（miRNA-495, miR-495）可通过调控细胞周期进程与细胞衰老，在抑制肝细胞癌细胞增殖中发挥重要作用。研究发现，miR-495在人体肝细胞癌组织及细胞系中呈低表达状态。在肝细胞癌细胞中过表达miR-495可产生显著的细胞增殖抑制效应，该效应由细胞周期阻滞与细胞衰老介导。经生物信息学预测与生物学实验验证，补体C1q肿瘤坏死因子相关蛋白3（CTRP3）为miR-495在肝细胞癌细胞中的潜在靶基因。利用小干扰RNA（small interfering RNA, siRNA）抑制CTRP3的表达后，肝细胞癌细胞同样呈现出与miR-495过表达相似的增殖抑制表型。在高表达miR-495的肝细胞癌细胞中重新过表达CTRP3，可抵消miR-495的抑癌作用并逆转细胞增殖抑制效应。上述结果充分表明，CTRP3是削弱miR-495在肝细胞癌细胞中抑癌功效的功能性靶基因。体内实验证实，过表达miR-495对异种移植瘤模型中的肝细胞癌具有显著的治疗效果。综上，本研究揭示了miR-495在抑制肝细胞癌增殖过程中的核心作用，其有望成为肝细胞癌临床治疗的全新策略。