Wnt7a, frequently silenced by CpG methylation, inhibits tumor growth and metastasis via suppressing epithelial-mesenchymal transition in gastric cancer

J Cell Biochem. 2019 Oct;120(10):18142-18151. doi: 10.1002/jcb.29118. Epub 2019 May 29.

Abstract

Wnt7a is a member of the Wnt family and has been reported to be involved in the carcinogenesis and progression of many types of human cancer. However, little is known about Wnt7a expression and function in gastric cancer (GC). In the present study, Wnt7a expression in GC tissues and cells was investigated, the correlation between Wnt7a expression and the prognosis was also examined. The effects of Wnt7a on proliferation, invasion, and metastasis were evaluated in vitro and in vivo. Furthermore, the expression of epithelial-mesenchymal transition (EMT) markers and hypermethylation of the Wnt7a promoter were both detected. Wnt7a was downregulated in GC and its expression was associated with poor prognosis of patients with GC. Moreover, upregulation of Wnt7a significantly suppressed the growth, invasion, and metastasis abilities of GC cells in vitro and in vivo. Mechanistically, Wnt7a was found to inhibit EMT process of GC cells. In addition, the reducing expression of Wnt7a was due to methylation of 5'-CpG island within the promoter. Furthermore, the tumor suppressor role of Wnt7a is independent of canonical Wnt/β-catenin signaling in GC cells. In conclusion, our findings demonstrated that Wnt7a could be used as a potential diagnostic marker and target for GC management.

Keywords: EMT; Wnt7a; gastric cancer; hypermethylation; metastasis; proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics*
  • CpG Islands / genetics
  • DNA Methylation / drug effects
  • DNA Methylation / genetics*
  • Decitabine / pharmacology
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Mice, Nude
  • Middle Aged
  • Neoplasm Metastasis
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / metabolism
  • Tumor Burden / genetics
  • Wnt Proteins / genetics*
  • Wnt Proteins / metabolism
  • Xenograft Model Antitumor Assays / methods

Substances

  • WNT7A protein, human
  • Wnt Proteins
  • Decitabine