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.
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA 98109, USA. bknudsen@fhcrc.org
Beatrice S
BS
Knudsen
Jared M
JM
Lucas
Ladan
L
Fazli
Sarah
S
Hawley
Seth
S
Falcon
Ilsa M
IM
Coleman
Dan B
DB
Martin
Chang
C
Xu
Lawrence D
LD
True
Martin E
ME
Gleave
Peter S
PS
Nelson
Gustavo E
GE
Ayala
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