Xiao Yao, Tian Qinggang, He Jiantai, Huang Ming, Yang Chao, Gong Liansheng
Department of Hepatobiliary and Pancreatic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
Department of General Surgery, The Fourth Affiliated Hospital of Baotou Medical College, Baotou, Inner Mongolia, People's Republic of China.
Onco Targets Ther. 2016 Jun 15;9:3535-44. doi: 10.2147/OTT.S106351. eCollection 2016.
MicroRNAs (miRs) have been demonstrated to play key roles in the development and progression of hepatocellular carcinoma (HCC). However, the regulatory mechanism of miR-503 in HCC has not been fully uncovered. In this study, we found that miR-503 was significantly downregulated in HCC tissues compared to nontumorous liver tissues. Moreover, lower miR-503 levels were associated with the malignant progression of HCC, and the expression of miR-503 was also decreased in several common HCC cell lines compared to normal human liver cell line THLE-3. Overexpression of miR-503 inhibited proliferation but induced apoptosis of LM3 and HepG2 cells. Bioinformatical analysis and luciferase reporter assay further identified insulin-like growth factor 1 receptor (IGF-1R) as a novel target of miR-503 in 293T cells. Moreover, overexpression of miR-503 led to a significant decrease in the protein levels of IGF-1R, while knockdown of miR-503 enhanced its protein levels in LM3 and HepG2 cells. Besides, overexpression of IGF-1R reversed the effects of miR-503-mediated HCC cell proliferation and apoptosis, indicating that IGF-1R acts as a downstream effector of miR-503 in HCC cells. Furthermore, IGF-1R was found to be significantly upregulated in HCC tissues compared to nontumorous liver tissues. In addition, the mRNA levels of IGF-1R were inversely correlated to the miR-503 levels in the HCC tissues. Thus, we demonstrate that miR-503 inhibits the proliferation and induces the apoptosis of HCC cells, partly at least, by directly targeting IGF-1R, and suggest that IGF-1R may serve as a promising target for the treatment of HCC.
微小RNA（miR）已被证明在肝细胞癌（HCC）的发生和发展中起关键作用。然而，miR - 503在HCC中的调控机制尚未完全阐明。在本研究中，我们发现与非肿瘤性肝组织相比，miR - 503在HCC组织中显著下调。此外，较低的miR - 503水平与HCC的恶性进展相关，并且与正常人肝细胞系THLE - 3相比，几种常见HCC细胞系中miR - 503的表达也降低。miR - 503的过表达抑制了LM3和HepG2细胞的增殖，但诱导了其凋亡。生物信息学分析和荧光素酶报告基因检测进一步确定胰岛素样生长因子1受体（IGF - 1R）是293T细胞中miR - 503的一个新靶点。此外，miR - 503的过表达导致IGF - 1R蛋白水平显著降低，而在LM3和HepG2细胞中敲低miR - 503则提高了其蛋白水平。此外，IGF - 1R的过表达逆转了miR - 503介导的HCC细胞增殖和凋亡的影响，表明IGF - 1R在HCC细胞中作为miR - 503的下游效应分子发挥作用。此外，与非肿瘤性肝组织相比，发现IGF - 1R在HCC组织中显著上调。另外，HCC组织中IGF - 1R的mRNA水平与miR - 503水平呈负相关。因此，我们证明miR - 503至少部分通过直接靶向IGF - 1R抑制HCC细胞的增殖并诱导其凋亡，并表明IGF - 1R可能是治疗HCC的一个有前景的靶点。
