Circular RNAs in Cell Cycle Regulation of Cancers.

Cancer has been one of the most problematic health issues globally. Typically, all cancers share a common characteristic or cancer hallmark, such as sustaining cell proliferation, evading growth suppressors, and enabling replicative immortality. Indeed, cell cycle regulation in cancer is often found to be dysregulated, leading to an increase in aggressiveness. These dysregulations are partly due to the aberrant cellular signaling pathway. In recent years, circular RNAs (circRNAs) have been widely studied and classified as one of the regulators in various cancers. Numerous studies have reported that circRNAs antagonize or promote cancer progression through the modulation of cell cycle regulators or their associated signaling pathways, directly or indirectly. Mostly, circRNAs are known to act as microRNA (miRNA) sponges. However, they also hold additional mechanisms for regulating cellular activity, including protein binding, RNA-binding protein (RBP) recruitment, and protein translation. This review will discuss the current knowledge of how circRNAs regulate cell cycle-related proteins through the abovementioned mechanisms in different cancers.

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

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.

Regulatory Functions and Mechanisms of Circular RNAs in Hepatic Stellate Cell Activation and Liver Fibrosis.

Chronic liver injury induces the activation of hepatic stellate cells (HSCs) into myofibroblasts, which produce excessive amounts of extracellular matrix (ECM), resulting in tissue fibrosis. If the injury persists, these fibrous scars could be permanent and disrupt liver architecture and function. Currently, effective anti-fibrotic therapies are lacking; hence, understanding molecular mechanisms that control HSC activation could hold a key to the development of new treatments. Recently, emerging studies have revealed roles of circular RNAs (circRNAs), a class of non-coding RNAs that was initially assumed to be the result of splicing errors, as new regulators in HSC activation. These circRNAs can modulate the activity of microRNAs (miRNAs) and their interacting protein partners involved in regulating fibrogenic signaling cascades. In this review, we will summarize the current knowledge of this class of non-coding RNAs for their molecular function in HSC activation and liver fibrosis progression.