Dual activation of Hedgehog and Wnt/β-catenin signaling pathway caused by downregulation of SUFU targeted by miRNA-150 in human gastric cancer

Yin Peng, Xiaojing Zhang, Huijuan Lin, Shiqi Deng, Ying Qin, Jieqiong He, Fan Hu, Xiaohui Zhu, Xianling Feng, Jian Wang, Yanjie Wei, Xinmin Fan, Huan Lin, Hassan Ashktorab, Duane Smoot, Yansi Lv, Song Li, Stephen J. Meltzer, Zhe Jin

Research output: Contribution to journalArticlepeer-review

Abstract

Mounting evidence has shown that miRNA-150 expression is upregulated in gastric cancer (GC) and is associated with gastric carcinogenesis, but the underlying oncogenic mechanism remains elusive. Here, we discovered that miRNA-150 targets the tumor suppressor SUFU to promote cell proliferation, migration, and the epithelial–mesenchymal transition (EMT) via the dual activation of Hedgehog (Hh) and Wnt signaling. MiRNA-150 was highly expressed in GC tissues and cell lines, and the level of this miRNA was negatively related to that of SUFU. In addition, both the miRNA-150 and SUFU levels were associated with tumor differentiation. Furthermore, miRNA-150 activated GC cell proliferation and migration in vitro. We found that miRNA-150 inhibitors repressed not only Wnt signaling by promoting cytoplasmic β-catenin localization, but also repressed Hh signaling and EMT. MiRNA-150 inhibition also resulted in significant tumor volume reductions in vivo, suggesting the potential application of miRNA-150 inhibitors in GC therapy. The expression of genes downstream of Hh and Wnt signaling was also reduced in tumors treated with miRNA-150 inhibitors. Notably, anti-SUFU siRNAs rescued the inhibitory effects of miRNA-150 inhibitors on Wnt signaling, Hh activation, EMT, cell proliferation, cell migration, and colony formation. Taken together, these findings indicate that miRNA-150 is oncogenic and promotes GC cell proliferation, migration, and EMT by activating Wnt and Hh signaling via the suppression of SUFU expression.

Original languageEnglish (US)
Pages (from-to)10749-10769
Number of pages21
JournalAging
Volume13
Issue number7
DOIs
StatePublished - Apr 15 2021

Keywords

  • EMT
  • SUFU
  • Wnt/β-catenin
  • hedgehog
  • miRNA-150

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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