Modulation of the TGF-β signaling pathway by long noncoding RNA in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a type of liver cancer with poor prognosis. There have been demonstrated to exist many possible mechanisms in HCC tumorigenesis, and recent investigations have provided some promising therapy targets. However, further mechanisms remain to be researched to improve the therapeutic strategy and diagnosis of HCC. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine which plays critical roles in networks of different cellular processes, and TGF-β signaling has been found to participate in tumor initiation and development of HCC in recent years. Moreover, among the molecules and signaling pathways, researchers paid more attention to lncRNAs (long non-coding RNAs), but the connection between lncRNAs and TGF-βremain poorly understood. In this review, we conclude the malignant procedure which lncRNAs and TGF-β involved in, and summarize the mechanisms of lncRNAs and TGF-βin HCC initiation and development. Furthermore, the interaction between lncRNA and TGF-β are paid more attention, and the potential therapy targets are mentioned.

Keywords: Hepatocellular carcinoma; Long noncoding RNA; TGF-β; Therapy target.

Fig. 1

Outline of TGF-β signaling pathway regulating HCC initiation and progression. TGF-β affect downstream molecules through canonical (SMADs) and noncanonical (AKT, KRAS, EGFR, STAT3 and PDGF) pathway to regulate several HCC-related processes. Many downstream molecules of TGF-β signaling pathway were reported to involve in the processes including liver fibrogenesis (p38, STAT3),tumor growth (Ki-67, MYC, Artemin and NF-kB) stemness (CD44, CD133, EpCAM and β-catenin), EMT (N-cadherin, AXL and Snail), apoptosis (EGFR, p-AKT) and immune inhibition (CD86, CD96, PD-1 and HLA-DR)

Fig. 2

Function of lncRNAs in regulating TGF-β signaling pathway to affect HCC tumorigenesis. In HCC, regulation of many related or downstream molecules in TGF-β signaling pathway were reported to be relevant to specific lncRNAs: upregulation of LTBP (MALAT1), upregulation of TGFβ1 (NEAT1, MEG3 and AWPPH), upregulation of SMADs (Lnc34a, KRT19, Lnc-LFAR1 and LINC01278), upregulation or stabilization of TGFBRs (NORAD, KRT19, HANR and H19). These lncRNAs affect TGF-β signaling pathway by many action sites of downstream molecules