Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
Oncol Res. 2023 Sep 15;31(6):989-1005. doi: 10.32604/or.2023.030395. eCollection 2023.
Hepatocellular carcinoma (HCC) is the leading cause of cancer death worldwide; nevertheless, current therapeutic options are limited or ineffective for many patients. Therefore, elucidation of molecular mechanisms in HCC biology could yield important insights for the intervention of novel therapies. Recently, various studies have reported dysregulation of long non-coding RNAs (lncRNAs) in the initiation and progression of HCC, including H19; however, the biological function of H19 in HCC remains unclear. Here, we show that knockdown of H19 disrupted HCC cell growth, impaired the G1-to-S phase transition, and promoted apoptosis, while overexpression of H19 yielded the opposite results. Screening for expression of cell cycle-related genes revealed a significant downregulation of CDK6 at both RNA and protein levels upon H19 suppression. Bioinformatic analysis of the H19 sequence and the 3' untranslated region (3' UTR) of transcripts showed several binding sites for microRNA-107 (miR-107), and the dual luciferase reporter assay confirmed their direct interaction with miR-107. Consistently, blockage of miR-107 activity alleviated the growth suppression phenotypes induced by H19 downregulation, suggesting that H19 serves as a molecular sponge for miR-107 to promote CDK6 expression and cell cycle progression. Together, this study demonstrates a mechanistic function of H19 in driving the proliferation of HCC cells and suggests H19 suppression as a novel approach for HCC treatment.
肝细胞癌（HCC）是全球癌症死亡的主要原因；然而，目前的治疗选择对许多患者来说是有限的或无效的。因此，阐明 HCC 生物学中的分子机制可以为新疗法的干预提供重要的见解。最近，各种研究报告称，长链非编码 RNA（lncRNA）在 HCC 的发生和发展中失调，包括 H19；然而，H19 在 HCC 中的生物学功能尚不清楚。在这里，我们表明 H19 的敲低破坏了 HCC 细胞的生长，损害了 G1 到 S 期的转变，并促进了细胞凋亡，而 H19 的过表达则产生了相反的结果。对细胞周期相关基因的表达进行筛选，发现 H19 抑制后 CDK6 的 RNA 和蛋白水平均显著下调。对 H19 序列和转录本的 3'非翻译区（3'UTR）进行生物信息学分析，发现几个 microRNA-107（miR-107）的结合位点，双荧光素酶报告基因实验证实了它们与 miR-107 的直接相互作用。一致地，miR-107 活性的阻断缓解了 H19 下调引起的生长抑制表型，表明 H19 作为 miR-107 的分子海绵促进 CDK6 表达和细胞周期进程。总之，这项研究证明了 H19 在驱动 HCC 细胞增殖中的机制功能，并表明抑制 H19 可能是 HCC 治疗的一种新方法。
