Long Noncoding RNA HOTTIP Promotes Mouse Hepatic Stellate Cell Activation via Downregulating miR-148a

Abstract

Background/Aims: HOTTIP is a critical modulator in human diseases including liver cancer, but its role and molecular biological mechanisms in liver fibrosis are still unclear. Methods: The expression profile of HOTTIP during the progression of liver fibrosis was detected in human liver samples and in CCl₄-treated mice using qRT-PCR. The expressing sh-HOTTIP adenoviral vector was used to reduce HOTTIP levels in vivo. Dual-Luciferase Reporter Assay was performed to validate the interaction between miR-148a and HOTTIP, TGFBR1, or TGFBR2. Results: HOTTIP expressions in fibrotic liver samples and cirrhotic liver samples were significantly upregulated compared with healthy liver controls, and cirrhotic samples exhibited the highest levels of HOTTIP. Moreover, HOTTIP expressions were substantially induced in the liver tissues and hepatic stellate cells (HSC) of CCl₄-treated mice. Ad-shHOTTIP delivery could alleviate CCl₄- induced liver fibrosis in mice. Down-regulation of HOTTIP inhibited the viability and activation of HSCs in vitro, and HOTTIP negatively regulated miR-148a expression in HSCs. miR-148a had a negative effect on HSC activation by targeting TGFBR1 and TGFBR2. Conclusion: HOTTIP is involved in the progression of liver fibrosis by promoting HSC activation. The high level of HOTTIP downregulates miR-148a, thus to increase the level of TGFBR1 and TGFBR2 and contribute to liver fibrosis.

The Roles and Mechanisms of lncRNAs in Liver Fibrosis

“…HOTTIP has been identified in human hepatocellular carcinoma (HCC) samples and is related to the disease outcomes and clinical progression of HCC patients [28]; in addition, HOTTIP is dysregulated in the early stage of human HCC [86]. HOTTIP is involved in regulating the progression of mouse liver fibrosis by promoting HSC activation as a ceRNA for miR-148a and miR-150 [35,61]. MiR-148a downregulation by HOTTIP plays a pivotal role in this pathogenic process [61].…”

“…HOTTIP is involved in regulating the progression of mouse liver fibrosis by promoting HSC activation as a ceRNA for miR-148a and miR-150 [35,61]. MiR-148a downregulation by HOTTIP plays a pivotal role in this pathogenic process [61]. Notably, high levels of HOTTIP downregulate miR-148a, increase the expression levels of the miR-148a targets TGF-beta receptor type-1 (TGFBR1) and TGF-beta receptor type-2 (TGFBR2) and thus contribute to liver fibrosis [61].…”

“…MiR-148a downregulation by HOTTIP plays a pivotal role in this pathogenic process [61]. Notably, high levels of HOTTIP downregulate miR-148a, increase the expression levels of the miR-148a targets TGF-beta receptor type-1 (TGFBR1) and TGF-beta receptor type-2 (TGFBR2) and thus contribute to liver fibrosis [61]. A later study showed that HOTTIP, as a ceRNA for miR-150, increases serum response factor (SRF) expression and induces mouse HSC activation [35].…”

“…To date, it has been found that lncRNAs cooperate with the TGF-β signalling pathway to regulate HSC activation and hepatic fibrosis. Inhibition of lncRNAs (HIF1A-AS [48], Gm5091 [77,78], and lincRNA-p21 [53]) and overexpression of lncRNAs (MALAT1 [92], SCARNA10 [51], Lnc-LFAR1 [34], and HOTTIP [61]) involved in the TGF-β signalling pathway could promote HSC activation and subsequently induce hepatic fibrosis. Thus, lncRNAs can reveal the mechanism by which the TGF-β signalling pathway is involved in regulating liver fibrosis based on noncoding RNAs.…”

Fibroblast Reprogramming in Gastrointestinal Cancer

“…Finally, long noncoding RNAs have been described as regulators of stromal activation in HSCs (Zhou et al, 2016). These can act through a circuit comprising also miRNAs, such as GAS5 that restrains hepatic fibrosis by targeting miR-23a through the PTEN/PI3K/Akt signaling pathway (Dong et al, 2019) and HOTTIP which promotes the activation of HSCs via the downregulation of miR-148a (Li et al, 2018).…”