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A more recent version of this article appeared on September 1, 2007

Published online before print August 9, 2007
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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070010

Accepted for publication May 24, 2007.

Article

c-Jun NH2 Terminal Kinase Activation and Decreased Expression of Mitogen-Activated Protein Kinase Phosphatase-1 Play Important Roles in Invasion and Angiogenesis of Urothelial Carcinomas

Keiji Shimada*, Mitsutoshi Nakamura*, Eiwa Ishida*, Tomonori Higuchi*, Motoyoshi Tanaka{dagger}, Ichiro Ota{ddagger}, and Noboru Konishi*@

From the Departments of Pathology,* and Otorhinolaryngology,{ddagger} Nara Medical University School of Medicine, Nara; and the Department of Urology,{dagger} Kinki University School of Medicine, Osaka, Japan

@ To whom correspondence should be addressed. E-mail: nkonishi{at}naramed-u.ac.jp.


  Abstract

We here examined whether c-Jun NH2 terminal kinase (JNK) might be involved in the progression of urothelial carcinomas. In vitro and in vivo invasion assays using Matrigel and chick embryo chorioallantoic membrane approaches showed constitutive activation of JNK to significantly increase two processes, invasion and angiogenesis, in the human urothelial carcinoma cell line kU-7, this being suppressed by a JNK inhibitor, SP600125, or cell-permeable peptides. In addition, we found that mitogen-activated protein kinase phosphatase (MKP)-1 functions as an endogenous inhibitor of JNK-mediated signals in urothelial carcinoma cells: chorioallantoic membrane assays showed UMUC14 cells with low MKP-1 expression to be more invasive and have pronounced angiogenesis compared to UMUC6 cells with high MKP-1. Furthermore, knockdown of the MKP-1 gene by siRNA transfection enhanced JNK activation in UMUC6 cells to the UMUC14 level. Immunohistochemically, JNK was found to be highly phosphorylated in high-grade and invasive carcinomas (≥pT2) as well as carcinoma in situ but not in low-grade and noninvasive phenotypes (pTa, pT1). In contrast, MKP-1 was much more expressed in low-grade/noninvasive cancers than with the high-grade/invasive phenotype, reversely correlating with phosphorylated JNK. Taken together, JNK activation and decreased expression of MKP-1 may play important roles in progression of urothelial carcinoma.




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