Maa Ming-Chei, Lee Jenq-Chang, Chen Yen-Jen, Chen Yun-Ju, Lee Yuch-Ching, Wang Shan-Tair, Huang Ching-Chung, Chow Nan-Haw, Leu Tzeng-Horng
Institute of Medical Science, China Medical University, Taichung 40402, Taiwan.
J Biol Chem. 2007 Jul 6;282(27):19399-409. doi: 10.1074/jbc.M610280200. Epub 2007 May 12.
In an attempt to study the role of Eps8 in human carcinogenesis, we observe that ectopic overexpression of Eps8 in SW480 cells (low Eps8 expression) increases cell proliferation. By contrast, expressing eps8 small interference RNA in SW620 and WiDr cells (high Eps8 expression) reduces their proliferation rate. Interestingly, attenuation of Eps8 decreases Src Pi-Tyr-416, Shc Pi-Tyr-317, and serum-induced FAK Pi-Tyr-397 and Pi-Tyr-861. Remarkably, by virtue of mammalian target of rapamycin/STAT3 Pi-Ser-727, Eps8 modulates FAK expression required for cell proliferation. Within 62% of colorectal tumor specimens examined, >2-fold enhancement of Eps8 as compared with their normal counterparts is observed, especially for those from the advanced stage. In agreement with the modulation of FAK by Eps8, the concomitant expression of these two proteins in tumor specimens is observed. Notably, Eps8 attenuation also impedes the motility of SW620 and WiDr cells, which can be rescued by ectopically expressed FAK. This finding discloses the indispensability of Eps8 and FAK in cell locomotion. These results provide a novel mechanism for Eps8-mediated FAK expression and activation in colon cancer cells.
为了研究Eps8在人类致癌过程中的作用，我们观察到在SW480细胞（Eps8低表达）中异位过表达Eps8会增加细胞增殖。相比之下，在SW620和WiDr细胞（Eps8高表达）中表达eps8小干扰RNA会降低它们的增殖速率。有趣的是，Eps8的减弱会降低Src磷酸化酪氨酸-416、Shc磷酸化酪氨酸-317以及血清诱导的粘着斑激酶磷酸化酪氨酸-397和磷酸化酪氨酸-861。值得注意的是，通过雷帕霉素哺乳动物靶标/信号转导和转录激活因子3磷酸化丝氨酸-727，Eps8调节细胞增殖所需的粘着斑激酶表达。在所检测的62%的结直肠癌标本中，观察到Eps8与其正常对应物相比增强了2倍以上，尤其是那些来自晚期的标本。与Eps8对粘着斑激酶的调节一致，在肿瘤标本中观察到这两种蛋白的共表达。值得注意的是，Eps8的减弱也会阻碍SW620和WiDr细胞的运动，这可以通过异位表达的粘着斑激酶来挽救。这一发现揭示了Eps8和粘着斑激酶在细胞运动中的不可或缺性。这些结果为Eps8介导的结肠癌细胞中粘着斑激酶的表达和激活提供了一种新机制。
