DNA methylation silences miR-132 in prostate cancer

被引:120
作者
Formosa, A. [1 ]
Lena, A. M. [2 ,3 ]
Markert, E. K. [4 ]
Cortelli, S. [1 ]
Miano, R. [5 ]
Mauriello, A. [6 ]
Croce, N. [1 ]
Vandesompele, J. [7 ,8 ]
Mestdagh, P. [7 ]
Finazzi-Agro, E. [5 ]
Levine, A. J. [9 ]
Melino, G. [2 ,3 ]
Bernardini, S. [1 ]
Candi, E. [2 ,3 ]
机构
[1] Univ Roma Tor Vergata, Dept Internal Med, Rome, Italy
[2] Univ Roma Tor Vergata, Dept Expt Med & Biochem Sci, Rome, Italy
[3] Univ Roma Tor Vergata, Biochem Lab IDI IRCCS, Rome, Italy
[4] Inst Adv Study, Simons Ctr Syst Biol, Princeton, NJ 08540 USA
[5] Univ Roma Tor Vergata, Policlin Tor Vergata, Div Urol, Dept Surg, Rome, Italy
[6] Univ Roma Tor Vergata, Dept Biopathol & Image Diagnost, Rome, Italy
[7] Ghent Univ Hosp, Ctr Med Genet Ghent, Ghent, Belgium
[8] Biogazelle, Zwijnaarde, Belgium
[9] Canc Inst New Jersey, New Brunswick, NJ USA
关键词
prostate cancer; miRNAs; miR-132; methylation; methylation-specific PCR; anoikis; MICRORNA EXPRESSION; TUMOR-SUPPRESSOR; CELL-ADHESION; GROWTH-FACTOR; EPIGENETICS; METASTASIS; HYPERMETHYLATION; CARCINOMA; APOPTOSIS; PROMOTES;
D O I
10.1038/onc.2012.14
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Silencing of microRNAs (miRNAs) by promoter CpG island methylation may be an important mechanism in prostate carcinogenesis. To screen for epigenetically silenced miRNAs in prostate cancer (PCa), we treated prostate normal epithelial and carcinoma cells with 5-aza-2'-deoxycytidine (AZA) and subsequently examined expression changes of 650 miRNAs by megaplex stemloop reverse transcription-quantitative PCR. After applying a selection strategy, we analyzed the methylation status of CpG islands upstream to a subset of miRNAs by methylation-specific PCR. The CpG islands of miR-18b, miR-132, miR-34b/c, miR-148a, miR-450a and miR-542-3p showed methylation patterns congruent with their expression modulations in response to AZA. Methylation analysis of these CpG islands in a panel of 50 human prostate carcinoma specimens and 24 normal controls revealed miR-132 to be methylated in 42% of human cancer cases in a manner positively correlated to total Gleason score and tumor stage. Expression analysis of miR-132 in our tissue panel confirmed its downregulation in methylated tumors. Re-expression of miR-132 in PC3 cells induced cell detachment followed by cell death (anoikis). Two pro-survival proteins-heparin-binding epidermal growth factor and TALIN2-were confirmed as direct targets of miR-132. The results of this study point to miR-132 as a methylation-silenced miRNA with an antimetastatic role in PCa controlling cellular adhesion. Oncogene (2013) 32, 127-134; doi:10.1038/onc.2012.14; published online 6 February 2012
引用
收藏
页码:127 / 134
页数:8
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