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Non-CpG island promoter hypomethylation and miR-149 regulate the expression of SRPX2 in colorectal cancer.

Abstract：

:Gene silencing by DNA hypermethylation of CpG islands is a well-characterized phenomenon in cancer. The effect of hypomethylation in particular of non-CpG island genes is much less well described. By genome-wide screening, we identified 105 genes in microsatellite stable (MSS) colorectal adenocarcinomas with an inverse correlation (Spearman's ρ ≤ -0.40) between methylation and expression. Of these, 35 (33%) were hypomethylated non-CpG island genes and two of them, APOLD1 (Spearman's ρ = -0.82) and SRPX2 (Spearman's ρ = -0.80) were selected for further analyses. Hypomethylation of both genes were localized events not shared by adjacent genes. A set of 662 FFPE DNA samples not only confirmed that APOLD1 and SRPX2 are hypomethylated in CRC but also revealed hypomethylation to be significantly (p < 0.01) associated with tumors being localized in the left side, CpG island methylator phenotype negative, MSS, BRAF wt, undifferentiated and of adenocarcinoma histosubtype. Demethylation experiments supported SRPX2 being epigenetically regulated via DNA methylation, whereas other mechanisms in addition to DNA methylation seem to be involved in the regulation of APOLD1. We further identified miR-149 as a potential novel post-transcriptional regulator of SRPX2. In carcinoma tissue, miR-149 was downregulated and inversely correlated to SRPX2 (ρ = -0.77). Furthermore, ectopic expression of miR-149 significantly reduced SRPX2 transcript levels. Our study highlights that in colorectal tumors, hypomethylation of non-CpG island-associated promoters deregulate gene expression nearly as frequent as do CpG-island hypermethylation. The hypomethylation of SRPX2 is focal and not part of a large block. Furthermore, it often translates to an increased expression level, which may be modulated by miR-149.

journal_name

Int J Cancer

journal_title

International journal of cancer

authors

Øster B,Linnet L,Christensen LL,Thorsen K,Ongen H,Dermitzakis ET,Sandoval J,Moran S,Esteller M,Hansen TF,Lamy P,COLOFOL steering group.,Laurberg S,Ørntoft TF,Andersen CL

doi

10.1002/ijc.27921

subject

Has Abstract

pub_date

2013-05-15 00:00:00

pages

2303-15

issue

eissn

0020-7136

issn

1097-0215

journal_volume

132

pub_type

杂志文章

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Non-CpG island promoter hypomethylation and miR-149 regulate the expression of SRPX2 in colorectal cancer.