The β-catenin/TCF-4-LINC01278-miR-1258-Smad2/3 axis promotes hepatocellular carcinoma metastasis

Oncogene. 2020 Jun;39(23):4538-4550. doi: 10.1038/s41388-020-1307-3. Epub 2020 May 5.

Abstract

Hepatocellular carcinoma (HCC) metastasis is largely responsible for HCC-associated recurrence and mortality. We aimed to identify metastasis-related long non-coding RNAs (lncRNAs) to understand the molecular mechanism of HCC metastasis. We first identified that miR-1258 was downregulated in HCC tissues both in The Cancer Genome Atlas (TCGA) and Sun Yat-sen University Cancer Center (SYSUCC) dataset. MiR-1258 expression negatively correlated with recurrence-free survival and overall survival of HCC patients. MiR-1258 overexpression inhibited migration and invasion of HCC cells both in vitro and in vivo, whereas miR-1258 downregulation promoted cell metastasis. Luciferase assays verified direct binding of miR-1258 to Smad2 and Smad3, thereby attenuating TGF-β/Smad signaling. We further established that lncRNA LINC01278 was a negative regulator of miR-1258. In vivo and in vitro assays demonstrated that LINC01278-mediated HCC metastasis was dependent on miR-1258 expression. Furthermore, miR-1258 downregulation in turn increased LINC01278 expression. We also observed that TCF-4 could bind to the LINC01278 promoter site. In addition, LINC01278 downregulation decreased migration and invasion of HCC cells induced by β-catenin and TGF-β1 both in vitro and in vivo. We uncovered a novel mechanism for β-catenin/TCF-4-LINC01278-miR-1258-Smad2/3 feedback loop activation in HCC metastasis, and the study indicated that LINC01278 could serve as a therapeutic target for HCC metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / pathology*
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Humans
  • Liver Neoplasms / pathology*
  • Lymphoid Enhancer-Binding Factor 1 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics
  • Neoplasm Metastasis / pathology*
  • Neoplasm Transplantation
  • RNA, Long Noncoding / genetics*
  • Smad2 Protein / metabolism
  • Smad3 Protein / metabolism
  • Transcription Factor 4 / genetics
  • Transcription Factor 4 / metabolism
  • Transforming Growth Factor beta / metabolism
  • Transplantation, Heterologous
  • Wnt Signaling Pathway / physiology*
  • Wnt1 Protein / metabolism
  • beta Catenin / metabolism

Substances

  • CTNNB1 protein, human
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • MIRN1258 microRNA, human
  • MicroRNAs
  • RNA, Long Noncoding
  • SMAD2 protein, human
  • SMAD3 protein, human
  • Smad2 Protein
  • Smad3 Protein
  • TCF4 protein, human
  • Transcription Factor 4
  • Transforming Growth Factor beta
  • WNT1 protein, human
  • Wnt1 Protein
  • beta Catenin