title: Activation of the osteopontin/matrix metalloproteinase-9 pathway correlates with prostate cancer progression.
abstract: 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.
authors.affiliation: Unit of Molecular Therapies, Department of Experimental Oncology, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Castellano
authors.forename: Grazia
authors.initials: G
authors.lastname: Malaponte
authors.forename: Maria C
authors.initials: MC
authors.lastname: Mazzarino
authors.forename: Mariangela
authors.initials: M
authors.lastname: Figini
authors.forename: Francesco
authors.initials: F
authors.lastname: Marchese
authors.forename: Pietro
authors.initials: P
authors.lastname: Gangemi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Travali
authors.forename: Franca
authors.initials: F
authors.lastname: Stivala
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
mesh_terms: 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*
chemical_list: D053495:Osteopontin; D020780:Matrix Metalloproteinase 9