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Journal of Biochemistry Advance Access originally published online on February 14, 2007
Journal of Biochemistry 2007 141(3):345-351; doi:10.1093/jb/mvm039
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© 2007 The Japanese Biochemical Society.

Smad4 is Essential for Down-regulation of E-cadherin Induced by TGF-ß in Pancreatic Cancer Cell Line PANC-1

Shinichi Takano1,2, Fumihiko Kanai3, Amarsanaa Jazag3, Hideaki Ijichi3, Jian Yao4, Hideoki Ogawa5, Nobuyuki Enomoto2, Masao Omata3 and Atsuhito Nakao1,5,*

1Department of Immunology, 2Department of Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan; 3Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 4Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, and 5Atopy Research Center, Juntendo University School of Medicine, Tokyo 113-8421, Japan

*To whom correspondence should be addressed. Tel: +81-55-273-6752, Fax: +81-55-273-9542, E-mail: anakao{at}yamanashi.ac.jp

Received November 2, 2006; Accepted January 9, 2007


  Abstract

Smad4 is a tumour suppressor gene frequently deleted in pancreatic cancer. To investigate the roles of Smad4 deficiency in invasive and matastatic capabilities of pancreatic cancer, we examined the effects of Smad4 deficiency on regulation of the invasion suppressor E-cadherin in pancreatic cancer cell line PANC-1. TGF-ß decreased expression of E-cadherin and ß-catenin proteins at the plasma membrane, increased Snail and Slug mRNA expression, and induced fibroblastoid morphology in PANC-1 cells. These effects of TGF-ß were abrogated in Smad4-knocked-down PANC-1 cells. We also found that TGF-ß-induced down-regulation of E-cadherin expression was partially inhibited in Snail- and Slug-knocked-down PANC-1 cells. Thus, Smad4 mediates down-regulation of E-cadherin induced by TGF-ß in PANC-1 cells, at least in part, through Snail and Slug induction. These results suggest that Smad4 deficiency observed in invasive and metastatic pancreatic cancer might not be linked to the loss of E-cadherin.

Key Words: pancreatic cancer, E-cadherin, Smad4, TGF-ß

Abbreviations: TGF-ß, transforming growth factor-ß; VEGF, vascular endothelial growth factor; siRNA, small-interfering RNA; EMT, epithelial mesenchymal transition


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