Activation of the osteopontin/matrix metalloproteinase-9 pathway correlates with prostate cancer progression.
OBJECTIVE
Prostate cancer remains the second most frequent cause of tumor-related deaths in the Western world. Additional markers for the identification of prostate cancer development and progression are needed. Osteopontin (OPN), which activates matrix metalloproteinases (MMP), is considered a prognostic biomarker in several cancers. "In silico" and experimental approaches were used to determine whether OPN-mediated MMP activation may be a signal of prostate cancer progression.


METHODS
Pearson correlation coefficients were computed for each OPN/MMP pair across seven publicly available prostate cancer gene expression data sets. Using Gene Set Enrichment Analysis, 101 cancer-related gene sets were analyzed for association with OPN and MMP-9 expression. OPN, MMP-9, MMP-2 tissue inhibitor of metalloproteinase-1 plasma levels, and MMP gelatinase activity were measured by ELISA and zymography in 96 and 92 patients with prostate cancer and benign prostatic hyperplasia, respectively, and 125 age-matched healthy men.


RESULTS
Computational analyses identified a significant correlation only between MMP-9 and OPN, and showed significant enrichment scores in "cell proliferation", "genes constituting the phosphoinositide-3-kinase predictor", "proliferation signature", and "tumor metastasis" gene sets in association with both OPN and MMP-9. Plasma analyses revealed a significant increase in OPN and MMP-9 levels and activity in patients with prostate cancer in association with clinical variables (prostate-specific antigen > 4 ng/mL and Gleason score > 7). Significant correlation between OPN and MMP-9 levels were also observed. Mean plasma levels of OPN and MMP-9 decreased in patients with prostate cancer within 6 months after prostatectomy.


CONCLUSIONS
The concordant computational and experimental data indicate that the extent of OPN pathway activation correlates with prostate cancer progression.
Castellano
Giancarlo
G
Unit of Molecular Therapies, Department of Experimental Oncology, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
Malaponte
Grazia
G
Mazzarino
Maria C
MC
Figini
Mariangela
M
Marchese
Francesco
F
Gangemi
Pietro
P
Travali
Salvatore
S
Stivala
Franca
F
Canevari
Silvana
S
Libra
Massimo
M
D000368:Aged; D018450:Disease Progression; D004789:Enzyme Activation / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D053495:Osteopontin; D020780:Matrix Metalloproteinase 9