Adaptor protein CRK induces epithelial-mesenchymal transition and metastasis of bladder cancer cells through HGF/c-Met feedback loop.
Adaptor protein CRK induces epithelial-mesenchymal transition and metastasis of bladder cancer cells through HGF/c-Met feedback loop.
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DOI：
10.1111/cas.12662
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发表时间：
2015-06
期刊：
影响因子：
5.7
通讯作者：
Tanaka S
中科院分区：
文献类型：
--
作者：
Matsumoto R;Tsuda M;Wang L;Maishi N;Abe T;Kimura T;Tanino M;Nishihara H;Hida K;Ohba Y;Shinohara N;Nonomura K;Tanaka S
我们以前曾报道过一种衔接蛋白CRK，包括CRK-I和CRK-II，在各种侵袭性人类癌症的恶性潜能中起着重要作用，这表明在广泛的癌症的分子靶向治疗中靶向CRK的有效性。然而，CRK在具有显著侵袭性、以远处转移和预后差为特征的人膀胱癌中的作用仍不清楚。在本研究中，免疫组织化学显示，与正常尿路上皮相比，人膀胱癌组织中CRK-I/-II显著增强，但CRK样蛋白没有增强。我们使用5637和UM-UC-3建立了CRK敲减的膀胱癌细胞，其显示出细胞迁移、侵袭和增殖的显著下降。值得注意的是，CRK的消除以肝细胞生长因子依赖性和非依赖性的方式抑制了c-Met和下游支架蛋白Gab 1的磷酸化。在上皮-间充质转化相关分子中，CRK消除上调了E-钙粘蛋白，而下调了N-钙粘蛋白、波形蛋白和Zeb 1。用c-Met抑制剂SU 11274处理后观察到类似的效果。CRK的消耗显著降低了5637和UM-UC-3的细胞增殖，与ERK活性降低一致。原位异种移植模型与生物发光成像显示，CRK敲除显着衰减不仅肿瘤体积，而且循环肿瘤细胞的数量，导致在一个完全废除的转移。总之，这些证据揭示了CRK通过肝细胞生长因子/c-Met/CRK反馈回路诱导上皮-间质转化在浸润性膀胱癌中的重要作用。因此，CRK可能是膀胱癌的一个有效分子靶点，特别是用于预防转移，从而解决临床上长期存在的关键问题。
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.
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DOI：
10.1186/bcr3183
发表时间：
2012-05-08
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Fathers KE;Bell ES;Rajadurai CV;Cory S;Zhao H;Mourskaia A;Zuo D;Madore J;Monast A;Mes-Masson AM;Grosset AA;Gaboury L;Hallet M;Siegel P;Park M
通讯作者：
Park M
影响因子：
64.8
作者：
MAYER, BJ;HAMAGUCHI, M;HANAFUSA, H
通讯作者：
HANAFUSA, H
DOI：
10.1016/j.bbrc.2007.08.106
发表时间：
2007-11-03
影响因子：
3.1
作者：
Wang, Lei;Tabu, Kouichi;Tanaka, Shinya
通讯作者：
Tanaka, Shinya
影响因子：
9.7
作者：
Nishihara, H;Tanaka, S;Nagashima, K
通讯作者：
Nagashima, K
影响因子：
44.1
作者：
Watanabe, Takuya;Tsuda, Masumi;Tanaka, Shinya
通讯作者：
Tanaka, Shinya