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）是全球范围内致死性恶性肿瘤之一，当前临床治疗手段的疗效有限且不尽如人意。微小RNA（MicroRNAs）在肿瘤发生发展过程中发挥关键调控作用，展现出极具潜力的临床治疗价值。本研究证实，微小RNA-495（miRNA-495，简称miR-495）可通过调控细胞周期进程与细胞衰老，显著抑制肝癌细胞的增殖。
miR-495在人体肝癌组织及细胞系中呈低表达状态。在肝癌细胞中过表达miR-495可强力抑制细胞增殖，该效应源于细胞周期阻滞与细胞衰老的共同作用。通过生物信息学预测与生物学实验验证，我们发现CTRP3是miR-495在肝癌细胞中的潜在靶基因。利用小干扰RNA（siRNA）抑制CTRP3的表达，可模拟miR-495过表达所带来的细胞增殖抑制效应。而在高表达miR-495的肝癌细胞中重新过表达CTRP3，则可抵消miR-495的作用并引发细胞生长抑制。
上述结果明确证实，CTRP3是削弱miR-495抑癌功能的功能性靶标。体内异种移植瘤实验表明，过表达miR-495对肝癌具有显著的治疗效果。综上，本研究揭示miR-495在抑制肝癌增殖过程中发挥关键作用，其有望成为肝癌临床治疗的全新策略。