Chung-Chi Hsu1, Wen-Ying Liao2, Kwang-Yu Chang3, Tze-Sian Chan2,4,5,6, Po-Jui Huang2,5,6, Chun-Ting Chiang7, Yan-Shen Shan8, Lin-Hsin Cheng2, Tai-Yan Liao2, Kelvin K Tsai9,10,11,12,13,14. 1. School of Medicine, College of Medicine, I-Shou University, Kaohsiung City, 824410, Taiwan. 2. Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wuxing St., Xinyi Dist., Taipei City, 110301, Taiwan. 3. National Institute of Cancer Research, National Health Research Institutes (NHRIs), Tainan City, 704016, Taiwan. 4. School of Medicine, College of Medicine, Taipei Medical University, Taipei City, 110301, Taiwan. 5. Division of Gastroenterology, Wan Fang Hospital, Taipei Medical University, Taipei City, 110301, Taiwan. 6. Integrative Therapy Center for Gastroenterological Cancers, Wan Fang Hospital, Taipei Medical University, Taipei City, 110301, Taiwan. 7. Department of Pathology, National Cheng-Kung University Hospital, Tainan City, 704302, Taiwan. 8. Department of Surgery, National Cheng-Kung University Hospital, Tainan City, 704302, Taiwan. 9. Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wuxing St., Xinyi Dist., Taipei City, 110301, Taiwan. tsaik@tmu.edu.tw. 10. National Institute of Cancer Research, National Health Research Institutes (NHRIs), Tainan City, 704016, Taiwan. tsaik@tmu.edu.tw. 11. Division of Gastroenterology, Wan Fang Hospital, Taipei Medical University, Taipei City, 110301, Taiwan. tsaik@tmu.edu.tw. 12. Integrative Therapy Center for Gastroenterological Cancers, Wan Fang Hospital, Taipei Medical University, Taipei City, 110301, Taiwan. tsaik@tmu.edu.tw. 13. TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei City, 110301, Taiwan. tsaik@tmu.edu.tw. 14. TMU and Affiliated Hospitals Pancreatic Cancer Group, Taipei Medical University, Taipei City, 110301, Taiwan. tsaik@tmu.edu.tw.
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.
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.
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