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

Cell Physiol Biochem. 2018;51(6):2814-2828. doi: 10.1159/000496012. Epub 2018 Dec 13.


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.

Keywords: HOTTIP; HSC activation; Liver fibrosis; miR-148a.

MeSH terms

  • Animals
  • Cells, Cultured
  • Down-Regulation*
  • Hepatic Stellate Cells / metabolism
  • Hepatic Stellate Cells / pathology*
  • Humans
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / pathology
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • RNA, Long Noncoding / genetics*
  • Up-Regulation


  • MicroRNAs
  • Mirn148 microRNA, mouse
  • RNA, Long Noncoding
  • long noncoding RNA HOTTIP, human