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Epigenetic silencing of SOCS3 identifies a subset of prostate cancer with an aggressive behavior
Author(s) -
Pierconti Francesco,
Martini Maurizio,
Pinto Francesco,
Cenci Tonia,
Capodimonti Sara,
Calarco Alessandro,
Bassi Pier Francesco,
Larocca Luigi Maria
Publication year - 2010
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21245
Subject(s) - socs3 , prostate cancer , dna methylation , methylation , cancer research , gene silencing , carcinogenesis , epigenetics , prostate , cancer , biology , immunohistochemistry , medicine , gene expression , immunology , gene , genetics , suppressor
BACKGROUND Chronic inflammation and subsequent tissutal alterations may play a key role in prostate carcinogenesis. In this way, molecular alterations of the suppressor of cytokine signaling 3 (SOCS3), one of the most important inhibitory molecule of inflammatory signal transduction circuitries, could contribute to explain the pleiotropic role of interleukin‐6 (IL‐6) in this type of cancer. METHODS We analyzed the methylation status and mRNA expression of SOCS3 in 20 benign prostate hyperplasias (BPH) and in 51 prostate cancer specimens. We analyzed the SOCS3 methylation status using methylation‐specific PCR. Hypermethylation was confirmed by sequencing after subcloning. Epigenetic silencing of this gene was also demonstrated by real‐time PCR and by immunohistochemestry. Results and correlation with clinical data were statistically analyzed. RESULTS We found that the promoter of SOCS3 was methylated in 39.2% of prostate cancer. On the contrary, all BPH and normal controls had an unmethylated pattern. Real‐time analysis showed that in methylated cases SOCS3 mRNA expression was reduced by three and four folds as compared to BPH and unmethylated cases, respectively. Interestingly, SOCS3 mRNA level was higher in unmethylated prostate cancer than in BPH. The immunohistochemical staining analysis for SOCS 3 confirmed mRNA results. Moreover, methylation of SOCS3 promoter significantly associated with intermediate–high grade Gleason score ( P = 0.0007) and with an unfavorable clinical outcome ( P = 0.0019). CONCLUSIONS Our data suggest that SOCS3 hypermethylation may be involved in the pathogenesis of prostate cancer and could identify a tumor subset with an aggressive behavior. Prostate 71:318–325, 2011. © 2010 Wiley‐Liss, Inc.