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J. Biol. Chem., Vol. 281, Issue 48, 36767-36775, December 1, 2006

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Involvement of p38 Mitogen-activated Protein Kinase in Lung Metastasis of Tumor Cells^*

Yuji Matsuo¹, Shinya Amano¹, Mitsuko Furuya^¶, Kana Namiki, Kanako Sakurai, Mariko Nishiyama, Tatsuhiko Sudo^||, Koichiro Tatsumi, Takayuki Kuriyama, Sadao Kimura, and Yoshitoshi Kasuya²

From the Departments of Biochemistry and Molecular Pharmacology, Respirology, and ^¶Molecular Pathology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan and the ^||Antibiotics Laboratory and Bioarchitect Research Group, RIKEN, Wako, Saitama 351-0198, Japan

To study the role of p38 mitogen-activated protein kinase (p38) activity during the process of metastasis, p38^+/- mice were subjected to an in vivo metastasis assay. The number of lung colonies of tumor cells intravenously injected in p38^+/- mice was markedly decreased compared with that in wild-type (WT) mice. On the other hand, the time-dependent increase in tumor volume after subcutaneous tumor cells transplantation was comparable between WT and p38^+/- mice. Platelets of p38^+/- mice were poorly bound to tumor cells in vitro and in vivo compared with those of WT mice. E- and P-selectin mRNAs were markedly induced in the lung after intravenous injection of tumor cells. However, the induction of these selectin mRNAs in p38^+/- mice was weaker than that in WT mice. Furthermore, the resting expression levels of E-selectin in lung endothelial cells and P-selectin in platelets of p38^+/- mice were suppressed compared with those of WT mice. The number of tumor cells attached on lung endothelial cells of p38^+/- mice was significantly reduced compared with that of WT mice. The transmigrating activity of tumor cells through lung endothelial cells of p38^+/- mice was similar to that of WT mice. These results suggest that p38 plays an important role in extravasation of tumor cells, possibly through regulating the formation of tumor-platelet aggregates and their interaction with the endothelium involved in a step of hematogenous metastasis.

Received for publication, May 8, 2006 , and in revised form, October 5, 2006.

^* This work was supported in part by Grant-in-Aid for Scientific Research 16616002 from the Ministry of Education, Science, Sports and Culture of Japan, by Grant-in-Aid RFTF96I00202 for "Research for the Future Program" from the Japan Society for Promotion of Science, and by the NISSAN Science Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These two authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Tel.: 81-43-226-2193; Fax: 81-43-226-2196; E-mail: kasuya{at}faculty.chiba-u.jp.

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