Activation of the Osteopontin/Matrix Metalloproteinase-9 Pathway Correlates with Prostate Cancer Progression
Activation of the Osteopontin/Matrix Metalloproteinase-9 Pathway Correlates with Prostate Cancer Progression
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DOI：
10.1158/1078-0432.ccr-08-0870
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发表时间：
2008-11-15
影响因子：
11.5
通讯作者：
Libra, Massimo
中科院分区：
文献类型：
--
作者：
Castellano, Giancarlo;Malaponte, Grazia;Libra, Massimo
目的：前列腺癌仍然是西方世界肿瘤相关死亡的第二大常见原因。需要用于鉴定前列腺癌发展和进展的其他标志物。骨桥蛋白（OPN）激活基质金属蛋白酶（MMP），被认为是几种癌症的预后生物标志物。“In silico”和实验方法用于确定OPN介导的MMP活化是否可能是前列腺癌进展的信号。实验设计：在7个公开可用的前列腺癌基因表达数据集上计算每个OPN/MMP对的Pearson相关系数。使用基因集富集分析，分析了101个癌症相关基因集与OPN和MMP-9表达的相关性。采用酶联免疫吸附试验（ELISA）和酶谱法分别检测96例前列腺癌和92例良性前列腺增生患者和125例年龄匹配的健康男性的OPN、MMP-9、MMP-2、MMP-1组织抑制因子（TIMP-1）血浆水平和MMP明胶酶活性。计算分析仅在MMP-9和OPN之间确定了显著相关性，并显示了“细胞增殖”的显著富集分数，与OPN和MMP-9相关的“构成磷酸肌醇-3-激酶预测因子的基因”、“增殖标记”和“肿瘤转移”基因组。血浆分析显示，前列腺癌患者的OPN和MMP-9水平和活性显著增加，与临床变量相关（前列腺特异性抗原> 4 ng/mL和Gleason评分> 7）。骨桥蛋白与基质金属蛋白酶-9水平之间也存在显著相关性。OPN和MMP-9的平均血浆水平下降，前列腺癌患者在6个月内prostectomy.Conclusions：一致的计算和实验数据表明，OPN通路激活的程度与前列腺癌的进展。
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.