A multi-mode Wnt- and stemness-regulatory module dictated by FOXM1 and ASPM isoform I in gastric cancer

Chung Chi Hsu, Wen Ying Liao, Kwang Yu Chang, Tze Sian Chan, Po Jui Huang, Chun Ting Chiang, Yan Shen Shan, Lin Hsin Cheng, Tai Yan Liao, Kelvin K. Tsai

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Background: Gastric cancer (GC) is the third leading cause of cancer mortality globally and a molecularly heterogeneous disease. Identifying the driver pathways in GC progression is crucial to improving the clinical outcome. Recent studies identified ASPM (abnormal spindle-like microcephaly-associated) and FOXM1 (Forkhead box protein M1) as novel Wnt and cancer stem cell (CSC) regulators; their pathogenetic roles and potential crosstalks in GC remain unclarified. Methods: The expression patterns of ASPM isoforms and FOXM1 were profiled in normal gastric epithelial and GC tissues. The functional roles of ASPM and FOXM1 in Wnt activity, cancer stemness and GC progression, and the underlying signaling processes were investigated. Results: Approximately one third of GC cells upregulate the expression of ASPM isoform I (ASPMiI) in their cytoplasm; the tumors with a high ASPMiI positive score (≥ 10%) are associated with a poor prognosis of the patients. Mechanistically, the molecular interplay among FOXM1, ASPMiI and DVL3 was found to converge on β-catenin to control the Wnt activity and the stemness property of GC cells. This multi-mode Wnt-regulatory module serves to reinforce Wnt signals in CSCs by transcriptional regulation (FOXM1–ASPM), protein–protein interactions (ASPMiI–DVL3–β-catenin), and nuclear translocation (FOXM1–β-catenin). Conclusions: This study illuminates a novel Wnt- and stemness-regulatory mechanism in GC cells and identifies a novel subset of FOXM1highASPMiIhigh GC with potential to guide Wnt- and stemness-related diagnostics and therapies.

Original languageEnglish
Pages (from-to)624-639
Number of pages16
JournalGastric Cancer
Volume24
Issue number3
DOIs
Publication statusPublished - May 2021

Keywords

  • ASPM
  • FOXM1
  • Gastric cancer
  • Stemness
  • Wnt

ASJC Scopus subject areas

  • Oncology
  • Gastroenterology
  • Cancer Research

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