Department of Pediatric Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China.
Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Biochem Biophys Res Commun. 2020 Apr 2;524(2):273-279. doi: 10.1016/j.bbrc.2020.01.034. Epub 2020 Jan 25.
Hepatocellular carcinoma (HCC) tumors evade death in part by downregulating expression of the tumor suppressor gene Interferon regulatory factor-1 (IRF-1). However, the molecular mechanisms accounting for IRF-1 suppression in HCC have not been well described. In this study, we identified a novel microRNA-301a (miR-301a) binding site in the 3'-untranslated region (3'- UTR) of the human IRF-1 gene and hypothesized a functional role for miR-301a in regulating HCC growth. We show that miR-301a is markedly upregulated in primary HCC tumors and HCC cell lines, while IRF-1 is down-regulated in a post-transcriptional manner. MiR-301a regulates basal and inducible IRF-1 expression in HCC cells with an inverse relationship between miR-301a and IRF-1 expression in HCC cells. Chronic hypoxia induces miR-301a in HCC in vitro and decreases IRF-1 expression. Finally, miR-301a inhibition increases apoptosis and decreases HCC cell proliferation. These findings suggest that targeting of IRF-1 by miR-301a contributes to the molecular basis for IRF-1 downregulation in HCC and provides new insight into the regulation of HCC by miRNAs.
肝细胞癌 (HCC) 肿瘤通过下调肿瘤抑制基因干扰素调节因子-1 (IRF-1) 的表达来逃避死亡。然而，HCC 中 IRF-1 抑制的分子机制尚未得到很好的描述。在这项研究中，我们在人类 IRF-1 基因的 3'-非翻译区 (3'-UTR) 中鉴定了一个新的 microRNA-301a (miR-301a) 结合位点，并假设 miR-301a 在调节 HCC 生长中具有功能作用。我们表明，miR-301a 在原发性 HCC 肿瘤和 HCC 细胞系中显著上调，而 IRF-1 以转录后方式下调。miR-301a 调节 HCC 细胞中的基础和诱导性 IRF-1 表达，miR-301a 和 HCC 细胞中的 IRF-1 表达呈负相关。慢性缺氧在体外诱导 HCC 中 miR-301a 的表达，并降低 IRF-1 的表达。最后，miR-301a 的抑制增加了 HCC 细胞的凋亡并减少了 HCC 细胞的增殖。这些发现表明，miR-301a 靶向 IRF-1 有助于 HCC 中 IRF-1 下调的分子基础，并为 miRNA 对 HCC 的调控提供了新的见解。
