PMID- 31465125 OWN - NLM STAT- MEDLINE DCOM- 20200420 LR - 20201210 IS - 1096-9896 (Electronic) IS - 0022-3417 (Print) IS - 0022-3417 (Linking) VI - 249 IP - 4 DP - 2019 Dec TI - The differential distributions of ASPM isoforms and their roles in Wnt signaling, cell cycle progression, and pancreatic cancer prognosis. PG - 498-508 LID - 10.1002/path.5341 [doi] AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and treatment-resistant malignancy. The lack of pathway-informed biomarkers hampers the development of rational diagnostics or therapies. Recently, the protein abnormal spindle-like microcephaly-associated (ASPM) was identified as a novel Wnt and stemness regulator in PDAC, while the pathogenic roles of its protein isoforms remain unclarified. We developed novel isoform-specific antibodies and genetic knockdown (KD) of putative ASPM isoforms, whereby we uncovered that the levels of ASPM isoform 1 (iI) and ASPM-iII are variably upregulated in PDAC cells. ASPM isoforms show remarkably different subcellular locations; specifically, ASPM-iI is exclusively localized to the cortical cytoplasm of PDAC cells, while ASPM-iII is predominantly expressed in cell nuclei. Mechanistically, ASPM-iI co-localizes with disheveled-2 and active beta-catenin as well as the stemness marker aldehyde dehydrogenase-1 (ALDH-1), and its expression is indispensable for the Wnt activity, stemness, and the tumorigenicity of PDAC cells. By contrast, ASPM-iII selectively regulates the expression level of cyclin E and cell cycle progression in PDAC cells. The expression of ASPM-iI and ASPM-iII displays considerable intratumoral heterogeneity in PDAC tissues and only that of ASPM-iI was prognostically significant; it outperformed ALDH-1 staining and clinico-pathological variables in a multivariant analysis. Collectively, the distinct expression patterns and biological functions of ASPM isoforms may illuminate novel molecular mechanisms and prognosticators in PDAC and may pave the way for the development of therapies targeting this novel oncoprotein. (c) 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. CI - (c) 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. FAU - Hsu, Chung-Chi AU - Hsu CC AD - Laboratory of Advanced Molecular Therapeutics, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. AD - Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. FAU - Liao, Wen-Ying AU - Liao WY AD - Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. FAU - Chan, Tze-Sian AU - Chan TS AD - Laboratory of Advanced Molecular Therapeutics, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. AD - Integrative Therapy Center for Gastroenterologic Cancers, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. AD - Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. AD - School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. FAU - Chen, Wei-Yu AU - Chen WY AD - Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. FAU - Lee, Chung-Ta AU - Lee CT AD - Department of Pathology, National Cheng-Kung University Hospital, Tainan, Taiwan. FAU - Shan, Yan-Shen AU - Shan YS AD - Department of Surgery, National Cheng-Kung University Hospital, Tainan, Taiwan. FAU - Huang, Po-Jui AU - Huang PJ AD - Laboratory of Advanced Molecular Therapeutics, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. AD - Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. AD - Integrative Therapy Center for Gastroenterologic Cancers, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. AD - Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. FAU - Hou, Ya-Chin AU - Hou YC AD - Department of Surgery, National Cheng-Kung University Hospital, Tainan, Taiwan. FAU - Li, Chi-Rong AU - Li CR AD - Department of Teaching and Research, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan. FAU - Tsai, Kelvin K AU - Tsai KK AUID- ORCID: 0000-0002-1612-2868 AD - Laboratory of Advanced Molecular Therapeutics, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. AD - Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. AD - Integrative Therapy Center for Gastroenterologic Cancers, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. AD - Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. AD - National Institute of Cancer Research, National Health Research Institutes (NHRIs), Zhunan, Taiwan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191023 PL - England TA - J Pathol JT - The Journal of pathology JID - 0204634 RN - 0 (ASPM protein, human) RN - 0 (CTNNB1 protein, human) RN - 0 (Cyclin E) RN - 0 (DVL2 protein, human) RN - 0 (Dishevelled Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (Protein Isoforms) RN - 0 (beta Catenin) RN - EC 1.2.1 (Aldehyde Dehydrogenase 1 Family) SB - IM CIN - J Pathol. 2020 Feb;250(2):123-125. PMID: 31595972 MH - Aldehyde Dehydrogenase 1 Family/metabolism MH - Carcinoma, Pancreatic Ductal/genetics/*metabolism/secondary MH - *Cell Cycle MH - Cell Line, Tumor MH - *Cell Proliferation MH - Cyclin E/metabolism MH - Dishevelled Proteins/metabolism MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Male MH - Middle Aged MH - Neoplastic Stem Cells/*metabolism/pathology MH - Nerve Tissue Proteins/genetics/*metabolism MH - Pancreatic Neoplasms/genetics/*metabolism/pathology MH - Protein Isoforms MH - *Wnt Signaling Pathway MH - beta Catenin/metabolism PMC - PMC6899738 OTO - NOTNLM OT - ASPM OT - Wnt OT - cell cycle OT - isoform OT - pancreatic cancer OT - stemness EDAT- 2019/08/30 06:00 MHDA- 2020/04/21 06:00 PMCR- 2019/12/08 CRDT- 2019/08/30 06:00 PHST- 2019/06/18 00:00 [received] PHST- 2019/08/16 00:00 [revised] PHST- 2019/08/23 00:00 [accepted] PHST- 2019/08/30 06:00 [pubmed] PHST- 2020/04/21 06:00 [medline] PHST- 2019/08/30 06:00 [entrez] PHST- 2019/12/08 00:00 [pmc-release] AID - PATH5341 [pii] AID - 10.1002/path.5341 [doi] PST - ppublish SO - J Pathol. 2019 Dec;249(4):498-508. doi: 10.1002/path.5341. Epub 2019 Oct 23.