Yang Xinchen, Yang Shikun, Song Jinhua, Yang Wenjie, Ji Yang, Zhang Feng, Rao Jianhua
Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Nanjing, China.
Cell Death Discov. 2021 Mar 15;7(1):47. doi: 10.1038/s41420-021-00440-0.
Growing evidence demonstrates that MicroRNAs (miRNAs) play an essential role in contributing to tumor development and progression. However, the underlying role and mechanisms of miR-23b-5p in hepatocellular carcinoma (HCC) formation remain unclear. Our study showed that miR-23b-5p was downregulated in the HCC tissues and cell lines, and lower expression of miR-23b-5p was associated with more severe tumor size and poorer survival. Gain- or loss-of-function assays demonstrated that miR-23b-5p induced G0/G1 cell cycle arrest and inhibited cell proliferation both in vitro and in vivo. qRT-PCR, western blot and luciferase assays verified that Mammalian transcription factor Forkhead Box M1 (FOXM1), upregulated in HCC specimens, was negatively correlated with miR-23b-5p expression and acted as a direct downstream target of miR-23b-5p. In addition, miR-23b-5p could regulate cyclin D1 and c-MYC expression by directly targeting FOXM1. Further study revealed that restoration of FOXM1 neutralized the cell cycle arrest and cell proliferation inhibition caused by miR-23b-5p. Taken together, our findings suggest that miR-23b-5p acted as a tumor suppressor role in HCC progression by targeting FOXM1 and may serve as a potential novel biomarker for HCC diagnosis and prognosis.
越来越多的证据表明，微小RNA（miRNA）在肿瘤发生和发展过程中起着至关重要的作用。然而，miR-23b-5p在肝细胞癌（HCC）形成中的潜在作用和机制仍不清楚。我们的研究表明，miR-23b-5p在HCC组织和细胞系中表达下调，且miR-23b-5p表达越低，肿瘤越大，生存率越低。功能获得或缺失实验表明，miR-23b-5p在体外和体内均可诱导G0/G1期细胞周期阻滞并抑制细胞增殖。qRT-PCR、蛋白质免疫印迹和荧光素酶实验证实，在HCC标本中上调的哺乳动物转录因子叉头框M1（FOXM1）与miR-23b-5p表达呈负相关，并且是miR-23b-5p的直接下游靶点。此外，miR-23b-5p可通过直接靶向FOXM1来调节细胞周期蛋白D1和c-MYC的表达。进一步研究发现，恢复FOXM1可抵消miR-23b-5p引起的细胞周期阻滞和细胞增殖抑制。综上所述，我们的研究结果表明，miR-23b-5p通过靶向FOXM1在HCC进展中发挥肿瘤抑制作用，可能作为HCC诊断和预后的潜在新型生物标志物。
