Department of Pathology, School of Medicine, Shandong University, Jinan, P. R. China.
Cancer Res. 2018 Oct 15;78(20):5877-5890. doi: 10.1158/0008-5472.CAN-18-1011. Epub 2018 Sep 5.
Long noncoding RNAs (lncRNA) are dysregulated in various human cancers and control tumor development and progression. However, the upstream mechanisms underlying their dysregulation remain unclear. Here, we demonstrate that the expression of hepatocyte nuclear factor 1 homeobox A antisense RNA 1 (HNF1A-AS1) is significantly upregulated in gastric cancer tissues. Overexpression of HNF1A-AS1 enhanced cell proliferation and promoted cell-cycle progression, whereas knockdown of HNF1A-AS1 elicited the opposite effects. Early growth response protein 1 (EGR1) directly bound the HNF1A-AS1 promoter region and activated its transcription. Overexpression of EGR1 enhanced cell proliferation and promoted cell-cycle promotion, similar to the function of HNF1A-AS1. HNF1A-AS1 functioned as competing endogenous RNA (ceRNA) by binding to miR-661, upregulating the expression of cell division cycle 34 (CDC34), which is a direct target of miR-661. EGR1 and HNF1A-AS1 enhanced the expression of cyclin-dependent kinase 2 (CDK2), CDK4, and cyclin E1 but inhibited the expression of p21 by promoting CDC34-mediated ubiquitination and degradation of p21. Taken together, these findings suggest that EGR1-activated HNF1A-AS1 regulates various pro- and antigrowth factors to promote the development of gastric cancer, implicating it as a possible target for therapeutic intervention in this disease. This study provides novel insights into mechanisms by which the noncoding RNA HNF1A-AS1 contributes to gastric cancer progression through modulation of the cell cycle. .
长链非编码 RNA（lncRNA）在各种人类癌症中失调，控制肿瘤的发生和发展。然而，其失调的上游机制尚不清楚。在这里，我们证明肝细胞核因子 1 同源盒 A 反义 RNA 1（HNF1A-AS1）在胃癌组织中的表达显著上调。HNF1A-AS1 的过表达增强了细胞增殖并促进了细胞周期进程，而 HNF1A-AS1 的敲低则产生了相反的效果。早期生长反应蛋白 1（EGR1）直接结合 HNF1A-AS1 启动子区域并激活其转录。EGR1 的过表达增强了细胞增殖并促进了细胞周期的促进，类似于 HNF1A-AS1 的功能。HNF1A-AS1 通过与 miR-661 结合作为竞争性内源 RNA（ceRNA）发挥作用，上调细胞分裂周期 34（CDC34）的表达，而 miR-661 是其直接靶标。EGR1 和 HNF1A-AS1 通过促进 CDC34 介导的 p21 的泛素化和降解来增强细胞周期蛋白依赖性激酶 2（CDK2）、CDK4 和细胞周期蛋白 E1 的表达，但抑制 p21 的表达。总之，这些发现表明 EGR1 激活的 HNF1A-AS1 通过调节各种促生长和抗生长因子来促进胃癌的发展，这表明它可能是该疾病治疗干预的潜在靶点。本研究为 HNF1A-AS1 通过调节细胞周期促进胃癌进展的机制提供了新的见解。
