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Journal of Biochemistry Advance Access published online on February 14, 2007
Journal of Biochemistry, doi:10.1093/jb/mvm039
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© 2007 The Japanese Biochemical Society

Smad4 is essential for downregulation 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, 5Atopy Research Center, Juntendo University School of Medicine, Tokyo 113-8421, Japan

Correspondence and reprint requests should be addressed to Atsuhito Nakao Department of Immunology, Faculty of Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi 409-3898, Japan 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 tumor 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 downregulation of E-cadherin expression was partially inhibited in Snail- and Slug-knocked down PANC-1 cells. Thus, Smad4 mediates downregulation 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: Smad4, TGF-ß, pancreatic cancer, E-cadherin


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