Long non-coding RNA H19 promotes proliferation in hepatocellular carcinoma cells via H19/miR-107/CDK6 axis

Abstract

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 CDK6 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.

MicroRNAs in hepatocellular carcinoma treatment: Charting the path forward

“…Another avenue of exploration may encompass interactions between miRNAs and other cellular proteins. For example, H19 (a long non-coding RNA) and circGPR37B (a circular RNA) have shown promise in reducing the effects of oncogenic miRNAs such as miR-107 and miR-4739, respectively[ 12 , 13 ].…”

“…They exert their effects through a multitude of routes. Examples include promotion of angiogenesis or loss of epithelial cell polarity ( e.g., miR-210 and miR-107), immune evasion ( e.g., miR-93-5p), and through unknown mechanisms ( e.g., miR-4739)[ 8 , 12 , 13 ]. As will be discussed later, many of these miRNAs will have relevant interactions with other proteins as well.…”

Circular RNAs in Cell Cycle Regulation of Cancers

“…For example, the miR-15 cluster promotes cell cycle arrest by targeting multiple key cell cycle regulators, including CDK1, CDK2, CDK6, cyclin D1, cyclin D3, and cyclin E1 [ 70 , 71 ]. Similarly, CDK6 expression was also found to be repressed by miR-107 [ 72 ].…”

CircMYBL2 facilitates hepatocellular carcinoma progression by regulating E2F1 expression

“…Consequently, the identification of treatment targets to elucidate potential carcinogenic mechanisms in HCC and the pursuit of more effective treatments are of paramount importance. To date, several studies have identified genes associated with the carcinogenesis of HCC and relevant regulators that may affect the transcription or translation of these genes [ 10 , 11 ]. However, the underlying molecular mechanisms remain elusive [ 12 – 14 ].…”