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Originally published online as doi:10.2353/ajpath.2008.071198 on June 26, 2008

Published online before print June 26, 2008
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(American Journal of Pathology. 2008;173:518-525.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.071198

Role of Human Aquaporin 5 In Colorectal Carcinogenesis

Sung Koo Kang*, Young Kwang Chae*, Janghee Woo*, Myoung Sook Kim*, Jong Chul Park*, Juna Lee*{dagger}, Jean Charles Soria§, Se Jin Jang, David Sidransky* and Chulso Moon*{ddagger}{dagger}

From the Department of Otolaryngology – Head and Neck Surgery;* Graduate Program in Human Genetics;{dagger} Department of Oncology{ddagger} and Sidney Kimmel Comprehensive Cancer Center; The Johns Hopkins Medical Institution, Baltimore, Maryland; Gustave Roussy Institute, Division of Cancer Medicine,§ Villejuif, France; Department of Pathology, Asan Medical Center, College of Medicine, Ulsan University, Seoul, Korea

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 (hAQP5) 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.






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Copyright © 2008 by the American Society for Investigative Pathology.