Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation

  1. Takeshi Miyatsuka1,6,
  2. Hideaki Kaneto1,
  3. Toshihiko Shiraiwa1,
  4. Taka-aki Matsuoka1,
  5. Kaoru Yamamoto1,
  6. Ken Kato1,
  7. Yumiko Nakamura1,
  8. Shizuo Akira2,
  9. Kiyoshi Takeda2,
  10. Yoshitaka Kajimoto1,
  11. Yoshimitsu Yamasaki1,
  12. Eric P. Sandgren3,
  13. Yoshiya Kawaguchi4,
  14. Christopher V.E. Wright5, and
  15. Yoshio Fujitani1,5,7
  1. 1 Department of Internal Medicine and Therapeutics
  2. 2 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan;
  3. 3 Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA;
  4. 4 Department of Surgery and Surgical Basic Science, Kyoto University, Kyoto 606-8507, Japan;
  5. 5 Vanderbilt Program in Developmental Biology and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA

Abstract

The transcription factor pancreatic and duodenal homeobox factor 1 (PDX-1) is expressed in pancreatic progenitor cells. In exocrine pancreas, PDX-1 is down-regulated during late development, while re-up-regulation of PDX-1 has been reported in pancreatic cancer and pancreatitis. To determine whether sustained expression of PDX-1 could affect pancreas development, PDX-1 was constitutively expressed in all pancreatic lineages by transgenic approaches. The transgenic pancreas was markedly small with the replacement of acinar cells by duct-like structures, accompanied by activated Stat3. Genetic ablation of Stat3 in the transgenic pancreas profoundly suppressed the metaplastic phenotype. These results provide a mechanism of pancreatic metaplasia by which persistent PDX-1 expression cell-autonomously induces acinar-to-ductal transition through Stat3 activation.

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  1. doi: 10.1101/gad.1412806 Genes & Dev. 20: 1435-1440 Copyright © 2006, Cold Spring Harbor Laboratory Press

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