Activation of the osteopontin/matrix metalloproteinase-9 pathway correlates with prostate cancer progression

Giancarlo Castellano, Grazia Malaponte, Maria C. Mazzarino, Mariangela Figini, Francesco Marchese, Pietro Gangemi, Salvatore Travali, Franca Stivala, Silvana Canevari, Massimo Libra

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Abstract

Purpose: 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. Experimental Design: 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.

Original languageEnglish
Pages (from-to)7470-7480
Number of pages11
JournalClinical Cancer Research
Volume14
Issue number22
DOIs
Publication statusPublished - Nov 15 2008

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Castellano, G., Malaponte, G., Mazzarino, M. C., Figini, M., Marchese, F., Gangemi, P., Travali, S., Stivala, F., Canevari, S., & Libra, M. (2008). Activation of the osteopontin/matrix metalloproteinase-9 pathway correlates with prostate cancer progression. Clinical Cancer Research, 14(22), 7470-7480. https://doi.org/10.1158/1078-0432.CCR-08-0870