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Ding, Li-Yun; Hou, Ya-Chin; Kuo, I-Ying; Hsu, Ting-Yi; Tsai, Tsung-Ching; Chang, Hsiu-Wei; Hsu, Wei-Yu; Tsao, Chih-Chieh; Tian, Chung-Chen; Wang, Po-Shun; Wang, Hao-Chen; Lee, Chung-Ta; Wang, Yi-Ching; Lin, Sheng-Hsiang; Hughes, Michael W.; Chuang, Woei-Jer; Lu, Pei-Jung; Shan, Yan-Shen; Huang, Po-Hsien

Epigenetic silencing of AATK in acinar to ductal metaplasia in murine model of pancreatic cancer

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  • Media type: E-Article
  • Title: Epigenetic silencing of AATK in acinar to ductal metaplasia in murine model of pancreatic cancer
  • Contributor: Ding, Li-Yun; Hou, Ya-Chin; Kuo, I-Ying; Hsu, Ting-Yi; Tsai, Tsung-Ching; Chang, Hsiu-Wei; Hsu, Wei-Yu; Tsao, Chih-Chieh; Tian, Chung-Chen; Wang, Po-Shun; Wang, Hao-Chen; Lee, Chung-Ta; Wang, Yi-Ching; Lin, Sheng-Hsiang; Hughes, Michael W.; Chuang, Woei-Jer; Lu, Pei-Jung; Shan, Yan-Shen; Huang, Po-Hsien
  • imprint: Springer Science and Business Media LLC, 2020
  • Published in: Clinical Epigenetics
  • Language: English
  • DOI: 10.1186/s13148-020-00878-6
  • ISSN: 1868-7075; 1868-7083
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Cancer subtype switching, which involves unclear cancer cell origin, cell fate decision, and transdifferentiation of cells within a confined tumor microenvironment, remains a major problem in pancreatic cancer (PDA).</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>By analyzing PDA subtypes in The Cancer Genome Atlas, we identified that epigenetic silencing of apoptosis-associated tyrosine kinase (<jats:italic>AATK</jats:italic>) inversely was correlated with mRNA expression and was enriched in the quasi-mesenchymal cancer subtype. By comparing early mouse pancreatic lesions, the non-invasive regions showed AATK co-expression in cells with acinar-to-ductal metaplasia, nuclear VAV1 localization, and cell cycle suppression; but the invasive lesions conversely revealed diminished AATK expression in those with poorly differentiated histology, cytosolic VAV1 localization, and co-expression of p63 and HNF1α. Transiently activated AATK initiates acinar differentiation into a ductal cell fate to establish apical-basal polarization in acinar-to-ductal metaplasia. Silenced AATK and ectopically expressed p63 and HNF1α allow the proliferation of ductal PanINs in mice.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Epigenetic silencing of <jats:italic>AATK</jats:italic> regulates the cellular transdifferentiation, proliferation, and cell cycle progression in converting PDA-subtypes.</jats:p> </jats:sec>
  • Access State: Open Access