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Carcinogenesis Advance Access published online on May 9, 2003
Carcinogenesis, doi:10.1093/carcin/bgg073
© 2003 by Oxford University Press
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© 2003 Oxford University Press

CANCER BIOLOGY

The role of P-glycoprotein in intestinal tumorigenesis: disruption of mdr1a suppresses polyp formation in ApcMin/+ mice

Yasushi Mochida 1, Ken-ichi Taguchi 2, Shuichi Taniguchi 1, Masazumi Tsuneyoshi 2, Hiroyuki Kuwano 3, Teruhisa Tsuzuki 4, Michihiko Kuwano 5, Morimasa Wada 1*

1 Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
2 Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
3 Department of Surgery I, Faculty of Medicine, Gunma University, Maebashi, Japan
4 Medical Biophysics and Radiation Biology, Kyushu University, Fukuoka, Japan
5 Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan

* Corresponding author. E-mail: wada{at}biochem1.med.kyushu-u.ac.jp.

Received 24 March 2003 ; revised 16 April 2003 ; accepted 22 April 2003

Abstract

P-glycoprotein (P-gp) mediates the active transport of various substrates including xenobiotics, and it thus has a protective function in various cell types and tissues/organs including the intestinal epithelium. However, whether or not P-gp plays a positive role in the intestinal tumorigenesis is unclear. We have introduced disrupted alleles of the murine P-gp gene, mdr1a, into ApcMin/+ mice to evaluate whether P-gp plays any role in intestinal carcinogenesis. Spontaneously occurring DNA damage was significantly increased in both the small and large intestine of mdr1a-/-, ApcMin/+ mice compared with mdr1a+/+, ApcMin/+ mice. Furthermore, we observed active proliferation and rapid migration/disappearance of enterocytes in the intestine of the compound mice deficient in mdr1a. Finally, we found that the number of polyps and cancers was markedly decreased in mdr1a-/-, ApcMin/+ mice (P=0.0016). P-gp thus appears to play a positive role during intestinal tumorigenesis.

ABC transporter, P-glycoprotein, DNA damage, ApcMin/+ mouse, intestinal tumor
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