1. Epigenetic silencing of AATK in acinar to ductal metaplasia in murine model of pancreatic cancer.
- Author
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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, and Huang, Po-Hsien
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PANCREATIC cancer , *METAPLASIA , *EPIGENETICS , *PROTEIN-tyrosine kinases , *CELL cycle - Abstract
Background: 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). Results: By analyzing PDA subtypes in The Cancer Genome Atlas, we identified that epigenetic silencing of apoptosis-associated tyrosine kinase (AATK) 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. Conclusion: Epigenetic silencing of AATK regulates the cellular transdifferentiation, proliferation, and cell cycle progression in converting PDA-subtypes. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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