Adaptor protein CRK induces epithelial-mesenchymal transition and metastasis of bladder cancer cells through HGF/c-Met feedback loop

Matsumoto, Ryuji; Tsuda, Masumi; Wang, Lei; Maishi, Nako; Abe, Takashige; Kimura, Taichi; Tanino, Mishie; Nishihara, Hiroshi; Hida, Kyoko; Ohba, Yusuke; Shinohara, Nobuo; Nonomura, Katsuya; Tanaka, Shinya

Adaptor protein CRK induces epithelial-mesenchymal transition and metastasis of bladder cancer cells through HGF/c-Met feedback loop

Matsumoto, Ryuji; Tsuda, Masumi; Wang, Lei et al.

Cancer science, 2015, 106(6), 709-717

Permalink : https://hdl.handle.net/2115/59617

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アクセス権	open access
URI	https://hdl.handle.net/2115/59617
タイトル	Adaptor protein CRK induces epithelial-mesenchymal transition and metastasis of bladder cancer cells through HGF/c-Met feedback loop
著者	Matsumoto, Ryuji ; Tsuda, Masumi ; Wang, Lei ; Maishi, Nako ; Abe, Takashige ; Kimura, Taichi ; Tanino, Mishie ; Nishihara, Hiroshi ; Hida, Kyoko ; Ohba, Yusuke ; Shinohara, Nobuo ; Nonomura, Katsuya ; Tanaka, Shinya
著者名 Matsumoto, Ryuji
e-Rad_Researcher 30431307 著者名 Tsuda, Masumi
著者名 Wang, Lei
e-Rad_Researcher 00632423 著者名 Maishi, Nako
e-Rad_Researcher 10399842 著者名 Abe, Takashige
e-Rad_Researcher 90435959 著者名 Kimura, Taichi
e-Rad_Researcher 90360908 著者名 Tanino, Mishie
e-Rad_Researcher 50322805 著者名 Nishihara, Hiroshi
e-Rad_Researcher 40399952 著者名 Hida, Kyoko
e-Rad_Researcher 30333503 著者名 Ohba, Yusuke
e-Rad_Researcher 90250422 著者名 Shinohara, Nobuo
e-Rad_Researcher 60113750 著者名 Nonomura, Katsuya
e-Rad_Researcher 70261287 著者名 Tanaka, Shinya
言語	英語
キーワード	Bladder cancer
	c-Met
	CRK
	EMT
	metastasis
発行日	2015-06
出版者	Wiley-Blackwell
収録物名	Cancer science
巻(号)	106(6)
ページ	709-717
抄録	We have previously reported that an adaptor protein CRK, including CRK-I and CRK-II, plays essential roles in the malignant potential of various aggressive human cancers, suggesting the validity of targeting CRK in molecular targeted therapy of a wide range of cancers. Nevertheless, the role of CRK in human bladder cancer with marked invasion, characterized by distant metastasis and poor prognosis, remains obscure. In the present study, immunohistochemistry indicated a striking enhancement of CRK-I/-II, but not CRK-like, in human bladder cancer tissues compared to normal urothelium. We established CRK-knockdown bladder cancer cells using 5637 and UM-UC-3, which showed a significant decline in cell migration, invasion, and proliferation. It is noteworthy that an elimination of CRK conferred suppressed phosphorylation of c-Met and the downstream scaffold protein Gab1 in a hepatocyte growth factor-dependent and -independent manner. In epithelial-mesenchymal transition-related molecules, E-cadherin was upregulated by CRK elimination, whereas N-cadherin, vimentin, and Zeb1 were downregulated. A similar effect was observed following treatment with c-Met inhibitor SU11274. Depletion of CRK significantly decreased cell proliferation of 5637 and UM-UC-3, consistent with reduced activity of ERK. An orthotopic xenograft model with bioluminescent imaging revealed that CRK knockdown significantly attenuated not only tumor volume but also the number of circulating tumor cells, resulted in a complete abrogation of metastasis. Taken together, this evidence uncovered essential roles of CRK in invasive bladder cancer through the hepatocyte growth factor/c-Met/CRK feedback loop for epithelial-mesenchymal transition induction. Thus, CRK might be a potent molecular target in bladder cancer, particularly for preventing metastasis, leading to the resolution of clinically longstanding critical issues.
資源タイプ	学術雑誌論文
出版タイプ	Version of Record
権利情報	Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
PISSN	1347-9032
関連情報 (isIdenticalTo)	出版社版DOI https://doi.org/10.1111/cas.12662