Molecular mechanisms of circular RNAs, transforming growth factor-β, and long noncoding RNAs in hepatocellular carcinoma

Abstract

At the heart of hepatocellular carcinoma (HCC) lies disruption of signaling pathways at the level of molecules, genes, and cells. Non-coding RNAs (ncRNAs) have been implicated in the disease progression of HCC. For instance, dysregulated expression of circular RNAs (circRNAs) has been observed in patients with HCC. As such, these RNAs are potential therapeutic targets and diagnostic markers for HCC. Long non-coding RNAs (lncRNAs), a type of ncRNA, have also been recognized to participate in the initiation and progression of HCC. Transforming growth factor-beta (TGF-β) is another element which is now recognized to play crucial roles in HCC. It has been implicated in many biological processes such as survival, immune surveillance, and cell proliferation. In HCC, TGF-β promotes disease progression by two mechanisms: an intrinsic signaling pathway and the extrinsic pathway. Through these pathways, it modulates various microenvironment factors such as inflammatory mediators and fibroblasts. An interesting yet-to-be resolved concept is whether the HCC-promoting role of TGF-β pathways is limited to a subset of HCC patients or it is involved in the whole process of HCC development. This review summarizes recent advancements to highlight the roles of circRNAs, lncRNAs, and TGF-β in HCC.

Keywords: TGF-β signaling; circular RNA; hepatocellular carcinoma; long non-coding RNA; pathogenesis of liver cancer.

Figure 1

Schematic description of the synthesis of circRNAs through a spliceosome‐guided splicing. The lariat intron formed out of the splicing event escapes normal degradation and debranching, and instead the 3′ “tail” downstream from the branchpoint is cut forming a circRNA

Figure 2

Schematic process of the formation of circRNA via back‐splicing process. A 3′ splice site (splice acceptor) of an upstream exon is joined to a 5′ splice site (splice donor) of a downstream exon through a process orchestrated by a spliceosome forming

Figure 3

A summary of TGF‐β signaling in HCC