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Carcinogenesis Advance Access published online on August 12, 2004
Carcinogenesis, doi:10.1093/carcin/bgh248
© 2004 by Oxford University Press
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Received March 31, 2004
Revised July 17, 2004
Accepted July 21, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Oncogenic Raf-1 regulates epithelial to mesenchymal transition via distinct signal transduction pathways in an immortalized mouse hepatic cell line

Mengdong Lan 1, Takashi Kojima 1*, Makoto Osanai 1, Hideki Chiba 1, Norimasa Sawada 1

1 Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan

* To whom correspondence should be addressed. E-mail: ktakashi{at}sapmed.ac.jp.


  Abstract

Epithelial to mesenchymal transition (EMT) is considered to be an important event during malignant tumor progression and metastasis. Although Raf/MEK/ERK signaling causes EMT, the mechanisms, including the signaling pathways, are as yet unclear. In the present study, we examined the effects of the signal transduction pathways on oncogenic Raf-1-induced EMT, using an immortalized mouse hepatic cell line, is characterized by down-regulation of adherens and tight junctions, and reorganization of actin. An active Raf-1 gene was introduced in to a mouse hepatic cell line, which was treated with the MAP-kinase inhibitor PD98059, the p38 MAP-kinase inhibitor SB203580, the PI3-kinase inhibitor LY294002 and the c-Src tyrosine-kinase inhibitor PP2. The expression and localization of adherens and tight junction proteins E-cadherin, occludin, ZO-1, claudin-1, -2 were determined by Western blotting, RT-PCR and immunocytochemistry. The barrier function of tight junctions was assessed by measurements of transepithelial electric resistance (TER) and permeability in terms of fluxes of [14C] mannitol and [14C] inulin. In the Raf-1-transfected cells, the expression of occludin and claudin-2 was markedly down-regulated at protein and mRNA levels, and the TER value was decreased while the permeability was increased. The distribution of ZO-1, pancadherin and F-actin was changed from linear to zipper-like structures at cell borders. In the Raf-1-transfected cells treated with PD98059 and SB203580 but not LY294002, expression and localization of claudin-2, but not occludin, were recovered together with the barrier function measured by the TER value. The distribution of ZO-1, pancadherin and F-actin was also recovered by treatment with PD98059 and SB203580 but not LY294002. The expression and localization of occludin were slightly recovered by treatment with PP2. Thus, oncogenic Raf-1 regulates EMT via distinct, MAP-kinase, p38 MAP-kinase and c-Src tyrosine-kinase signal pathways in the mouse hepatic cell line.

Keywords: tight junctions; adherens junctions; EMT; signal transduction; hepatocytes.
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