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(American Journal of Pathology. 2005;167:255-266.)
© 2005 American Society for Investigative Pathology

Regulation of Hepatocyte Activator Inhibitor-1 Expression by Androgen and Oncogenic Transformation in the Prostate

Beatrice S. Knudsen*, Jared M. Lucas{dagger}, Ladan Fazli{ddagger}, Sarah Hawley*, Seth Falcon*, Ilsa M. Coleman{dagger}, Dan B. Martin§, Chang Xu*, Lawrence D. True, Martin E. Gleave{ddagger}, Peter S. Nelson{dagger} and Gustavo E. Ayala||

From the Divisions of Public Health Sciences,* Human Biology,{dagger} and Clinical Research,§ Fred Hutchinson Cancer Research Center, Seattle, Washington; the Department of Pathology, University of Washington, Seattle, Washington; the Department of Pathology,|| Baylor College of Medicine, Houston, Texas; and the Prostate Center at Vancouver General Hospital,{ddagger} Vancouver, British Columbia, Canada

Hepatocyte activator inhibitor-1 (HAI-1) is a transmembrane serine protease inhibitor that regulates the conversion of latent to active hepatocyte growth factor (HGF). Studies supporting a role for the HGF pathway in prostate carcinogenesis prompted an analysis of HAI-1 expression in the prostate. Here we analyze the regulation of HAI-1 expression by androgen, oncogenic transformation, and cancer progression. Immunohistochemical analysis revealed that HAI-1 expression was restricted to prostate epithelium, where staining occurred primarily in basal and atrophic luminal epithelial cells. Compared to normal glands, HAI-1 expression was significantly increased in localized prostate cancer and was present in most prostate cancer metastases. HAI-1 protein expression levels were sensitive to androgen in normal epithelium but not in cancer. Although androgen did not increase HAI-1 protein expression levels in LNCaP cells, it decreased HAI-1 surface expression, consistent with previous data from our group (Martin DB, Gifford DR, Wright ME, Keller A, Yi E, Goodlett DR, Aebersold R, Nelson PS: Quantitative proteomic analysis of proteins released by neoplastic prostate epithelium. Cancer Res 2004, 64:347–355). HAI-1 overexpression in cancer was predictive of prostate-specific antigen recurrence (relative risk, 1.24). These results suggest that HAI-1 regulates the HGF Met axis on prostate epithelial cells and influences HGF mediated tumor invasion and metastasis.




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