Regulation of hepatocyte activator inhibitor-1 expression by androgen and oncogenic transformation in the prostate.
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.
Knudsen
Beatrice S
BS
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA 98109, USA. bknudsen@fhcrc.org
Lucas
Jared M
JM
Fazli
Ladan
L
Hawley
Sarah
S
Falcon
Seth
S
Coleman
Ilsa M
IM
Martin
Dan B
DB
Xu
Chang
C
True
Lawrence D
LD
Gleave
Martin E
ME
Nelson
Peter S
PS
Ayala
Gustavo E
GE
D000728:Androgens / Q000378:metabolism* / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000032:analysis*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000378:metabolism; D011467:Prostate / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000378:metabolism*; D040081:Protein Array Analysis; D015203:Reproducibility of Results; D015842:Serine Proteinase Inhibitors / Q000096:biosynthesis*
D000728:Androgens; D014408:Biomarkers, Tumor; D015842:Serine Proteinase Inhibitors; D017228:Hepatocyte Growth Factor; D017430:Prostate-Specific Antigen