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

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Title: Adaptor protein CRK induces epithelial-mesenchymal transition and metastasis of bladder cancer cells through HGF/c-Met feedback loop
Authors: Matsumoto, Ryuji Browse this author
Tsuda, Masumi Browse this author →KAKEN DB
Wang, Lei Browse this author
Maishi, Nako Browse this author →KAKEN DB
Abe, Takashige Browse this author →KAKEN DB
Kimura, Taichi Browse this author →KAKEN DB
Tanino, Mishie Browse this author →KAKEN DB
Nishihara, Hiroshi Browse this author →KAKEN DB
Hida, Kyoko Browse this author →KAKEN DB
Ohba, Yusuke Browse this author →KAKEN DB
Shinohara, Nobuo Browse this author →KAKEN DB
Nonomura, Katsuya Browse this author →KAKEN DB
Tanaka, Shinya Browse this author →KAKEN DB
Keywords: Bladder cancer
c-Met
CRK
EMT
metastasis
Issue Date: Jun-2015
Publisher: Wiley-Blackwell
Journal Title: Cancer science
Volume: 106
Issue: 6
Start Page: 709
End Page: 717
Publisher DOI: 10.1111/cas.12662
Abstract: 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.
Rights: http://creativecommons.org/licenses/by-nc-nd/4.0/
Type: article
URI: http://hdl.handle.net/2115/59617
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 田中 伸哉

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