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.
We here examined whether c-Jun NH(2) 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.
Shimada
Keiji
K
Department of Pathology, Nara Medical University School of Medicine, Shijo-cho, Kashihara city, Nara, 634-8521, Japan.
Nakamura
Mitsutoshi
M
Ishida
Eiwa
E
Higuchi
Tomonori
T
Tanaka
Motoyoshi
M
Ota
Ichiro
I
Konishi
Noboru
N
D000818:Animals; D045744:Cell Line, Tumor; D002642:Chick Embryo; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014571:Urologic Neoplasms / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D019459:Urothelium / Q000166:cytology / Q000201:enzymology / Q000473:pathology*
D034741:RNA, Small Interfering; D048031:JNK Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1
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