Aberrant expression of Wnt/β-catenin signaling pathway genes in aggressive malignant gastric gastrointestinal stromal tumors

Keiichi Fujiya, Keiichi Ohshima, Yuko Kitagawa, Keiichi Hatakeyama, Takeshi Nagashima, Daisuke Aizawa, Takeshi Sugino, Kenichi Urakami, Ken Yamaguchi, Masanori Terashima

Research output: Contribution to journalArticle

Abstract

Introduction: Recent reports on gene expression profiling (GEP) show several genes associated with malignant progression of GIST. However, genes associated with malignant transformation have not been clarified. Here, we aimed to reveal distinct genes in aggressive malignant GIST, using comprehensive gene expression analysis. Materials and methods: We investigated GEP obtained by microarrays for 43 gastric GISTs, which mostly harbored KIT and PDGFRA mutations and integrated clinicopathological risk information. RT-PCR and immunohistochemistry were performed for FZD7, a receptor of Wnt ligands. Results: GEP divided 43 gastric GISTs into two clusters. A cluster included seven of eight high-risk GISTs (88%) in modified NIH classification and was defined as high-risk cluster; the other cluster was defined as low-risk cluster. The number of probes with over 3-fold changes between the two clusters was 1,177, in which probes corresponding to 16 oncogenes were included. Genes involved in the Wnt signaling pathway were the most abundant among the 16 oncogenes. Focusing on 73 Wnt signaling pathway genes of the 21,578 probes, 12 upregulated and 5 downregulated genes were found in the high-risk cluster. Major cascade genes promoting the Wnt/β-catenin signaling pathway, including WNT11, FZD family, and DVL2, were upregulated in the high-risk cluster. SNAI1, SNAI2, and BIRC5, which are activated by this pathway and increase cell proliferation, were also upregulated. These gene expression alterations were consistent in the positive direction of this pathway. GISTs in high-risk cluster strongly expressed FZD7. Conclusion: Wnt/β-catenin signaling pathway may play an important role in malignant transformation of indolent GIST.

Original languageEnglish
Pages (from-to)1080-1087
Number of pages8
JournalEuropean Journal of Surgical Oncology
Volume46
Issue number6
DOIs
Publication statusPublished - 2020 Jun

Keywords

  • FZD
  • Gene expression profiling
  • Malignant GIST
  • Wnt pathway
  • β-catenin

ASJC Scopus subject areas

  • Surgery
  • Oncology

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  • Cite this

    Fujiya, K., Ohshima, K., Kitagawa, Y., Hatakeyama, K., Nagashima, T., Aizawa, D., Sugino, T., Urakami, K., Yamaguchi, K., & Terashima, M. (2020). Aberrant expression of Wnt/β-catenin signaling pathway genes in aggressive malignant gastric gastrointestinal stromal tumors. European Journal of Surgical Oncology, 46(6), 1080-1087. https://doi.org/10.1016/j.ejso.2020.02.036