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Research Paper|Volume 13, Issue 7|pp 10749—10769

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

Yin Peng1,2, Xiaojing Zhang1,2,3, Huijuan Lin4,5, Shiqi Deng1, Ying Qin6, Jieqiong He1, Fan Hu1, Xiaohui Zhu1, Xianling Feng1, Jian Wang5, Yanjie Wei7, Xinmin Fan1, Huan Lin8, Hassan Ashktorab9, Duane Smoot10, Yansi Lv1, Song Li11, Stephen J. Meltzer12, Zhe Jin1,2
  • 1Guangdong Key Laboratory for Genome Stability and Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen 518060, Guangdong, P.R. China
  • 2Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Health Science Center, Shenzhen University, Shenzhen 518060, Guangdong, P.R. China
  • 3Department of Pathology, Guangdong Province Key Laboratory of Molecular Oncologic Pathology, Guangzhou 510515, Guangdong, P.R. China
  • 4Department of Ultrasound, Guangdong Women and Children Hospital, Guangzhou 510000, Guangdong, P.R. China
  • 5Department of Pathology and Pathophysiology, Guangzhou Medical University, Guangzhou 510000, Guangdong, P.R. China
  • 6Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shenzhen University, Shenzhen 518000, Guangdong, P.R. China
  • 7Center for High Performance Computing, Shenzhen Institutes of Advanced Technology, Shenzhen 518000, Guangdong, P.R. China
  • 8Department of Vascular Surgery, The First Affiliated Hospital of Shenzhen University, Shenzhen 518060, Guangdong, P.R. China
  • 9Department of Medicine and Cancer Center, Howard University, College of Medicine, Washington, DC 20060, USA
  • 10Department of Medicine, Meharry Medical Center, Nashville, TN 37208, USA
  • 11Shenzhen Science and Technology Development Exchange Center, Shenzhen 518060, Guangdong, P.R. China
  • 12Department of Medicine, GI Division, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA
Received: June 26, 2020Accepted: October 22, 2020Published: April 12, 2021
https://doi.org/10.18632/aging.202895

Copyright: © 2021 Peng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.