Waly Amr A, El-Ekiaby Nada, Assal Reem A, Abdelrahman Mohamed M, Hosny Karim A, El Tayebi Hend M, Esmat Gamal, Breuhahn Kai, Abdelaziz Ahmed I
The Molecular Pathology Research Group, German University in Cairo, Cairo, Egypt.
School of Medicine, Newgiza University, Cairo, Egypt.
Front Physiol. 2019 Jan 24;9:1918. doi: 10.3389/fphys.2018.01918. eCollection 2018.
miR-let-7a is a tumor suppressor miRNA with reduced expression in most cancers. Methylation of gene was reported to be the cause of this suppression in several cancers; however, it was not explicitly investigated in hepatocellular carcinoma (HCC). We aimed at investigating miR-let-7a expression and molecular mode in HCC, identifying drug-targetable networks, which might be affected by its abundance. Our results illustrated a significant repression of miR-let-7a, which correlated with hypermethylation of its gene of origin . This was further supported by the induction of miR-let-7a expression upon treatment of HCC cells with a DNA-methyltransferase inhibitor. Using a computational approach, insulin-like growth factor (IGF)-II and IGF-2 mRNA binding proteins (IGF2BP)-2/-3 were identified as potential targets for miR-let-7a that was further confirmed experimentally. Indeed, miR-let-7a mimics diminished IGF-II as well as IGF2BP-2/-3 expression. Direct binding of miR-let-7a to each respective transcript was confirmed using a luciferase reporter assay. In conclusion, this study suggests that DNA hypermethylation leads to epigenetic repression of miR-let-7a in HCC cells, which induces the oncogenic IGF-signaling pathway.
miR-let-7a是一种肿瘤抑制性微小RNA（miRNA），在大多数癌症中表达降低。据报道，在几种癌症中，该基因的甲基化是这种抑制作用的原因；然而，在肝细胞癌（HCC）中尚未对此进行明确研究。我们旨在研究HCC中miR-let-7a的表达和分子模式，确定可能受其丰度影响的可药物靶向网络。我们的结果表明miR-let-7a存在显著抑制，这与其起源基因的高甲基化相关。用DNA甲基转移酶抑制剂处理HCC细胞后miR-let-7a表达的诱导进一步支持了这一点。使用计算方法，胰岛素样生长因子（IGF）-II和IGF-2 mRNA结合蛋白（IGF2BP）-2/-3被确定为miR-let-7a的潜在靶点，并通过实验进一步证实。事实上，miR-let-7a模拟物减少了IGF-II以及IGF2BP-2/-3的表达。使用荧光素酶报告基因检测证实了miR-let-7a与每个相应转录本的直接结合。总之，本研究表明DNA高甲基化导致HCC细胞中miR-let-7a的表观遗传抑制，从而诱导致癌的IGF信号通路。
