Role of human aquaporin 5 in colorectal carcinogenesis
Role of human aquaporin 5 in colorectal carcinogenesis
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DOI：
10.2353/ajpath.2008.071198
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发表时间：
2008-08-01
影响因子：
6
通讯作者：
Moon, Chulso
中科院分区：
文献类型：
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作者：
Kang, Sung Koo;Chae, Young Kwang;Moon, Chulso
虽然已经报道了几种水通道蛋白(AQPs)在不同类型的人类癌症中的过度表达，但AQPs在肿瘤发生中的作用尚不清楚。通过免疫组织化学方法，我们发现AQP5蛋白在62.8%(59/94)的结肠癌组织中表达，并与肝转移有关。然后我们证明了过表达人AQP5(BAQP5)可以诱导结肠癌细胞的增殖。野生型hAQP5的过表达促进了HCT116结肠癌细胞外信号调节激酶-1/2的增殖和磷酸化，而在hAQP5突变体(N185D和S156A)中这些现象被减弱，这表明AQP5的膜结合和丝氨酸/苏氨酸磷酸化都是正常发挥作用所必需的。有趣的是，AQP1和AQP3的过表达在细胞外信号调节激酶-1/2的磷酸化方面没有差异，这表明AQP5可能与AQP1不同，可能参与了信号转导。此外，hAQP5过表达细胞通过形成与细胞周期蛋白D1和CDK4的核复合体，增加视网膜母细胞瘤蛋白的磷酸化。小干扰RNA分析证实，hAQP5激活了RAS信号通路。这些数据不仅描述了hAQP5在结直肠癌发生过程中的诱导表达，而且通过hAQP5与RAS/细胞外信号调节激酶/视网膜母细胞瘤蛋白信号通路的相互作用，为结肠癌的发生提供了分子机制，证实了hAQP5是一个新的治疗靶点。
While overexpression of several aquaporins (AQPs) has been reported in different types of human cancer, the role of AQPs in carcinogenesis has not been clearly defined. Here, by immunochemistry, we have found expression of AQP5 protein in 62.8% (59/94) of resected colon cancer tissue samples as well as association of AQP5 with liver metastasis. We then demonstrated that overexpression of human AQP5 (bAQP5) induces cell proliferation in colon cancer cells. Overexpression of wild-type hAQP5 increased proliferation and phosphorylation of extracellular signal-regulated kinase-1/2 in HCT116 colon cancer cells whereas these phenomena in hAQP5 mutants (N185D and S156A) were diminished, indicating that both membrane association and serine/threonine phosphorylation of AQP5 are required for proper function. Interestingly, overexpression of AQP1 and AQP3 showed no differences in extracellular signal-regulated kinase-1/2 phosphorylation, suggesting that AQP5, unlike AQP1, may be involved in signal transduction. Moreover, hAQP5-overexpressing cells showed an increase in retinoblastoma protein phosphorylation through the formation of a nuclear complex with cyclin D1 and CDK4. Small interfering RNA analysis confirmed that hAQP5 activates the Ras signaling pathway. These data not only describe the induction of hAQP5 expression during colorectal carcinogenesis but also provide a molecular mechanism for colon cancer development through the interaction of hAQP5 with the Ras/extracellular signal-regulated kinase/retinoblastoma protein signaling pathway, identifying hAQP5 as a novel therapeutic target.