Abstract
BackgroundAltered expression of microRNAs (miRNAs) commonly accompanies colorectal (CRC) and endometrial carcinoma (EC) development, but the underlying mechanisms and clinicopathological correlations remain to be clarified. We focused on epigenetic mechanisms and aimed to explore if DNA methylation patterns in tumors depend on DNA mismatch repair (MMR) status, sporadic vs. Lynch-associated disease, and geographic origin (Finland vs. Australia). Treatment of cancer cell lines with demethylating agents revealed 109 significantly upregulated miRNAs. Seven met our stringent criteria for possible methylation-sensitive miRNAs and were used to screen patient specimens (205 CRCs and 36 ECs) by methylation-specific multiplex ligation-dependent probe amplification.ResultsThree miRNAs (129-2, 345, and 132) with low methylation levels in normal tissue and frequent hypermethylation in tumors were of particular interest. Hypermethylation of miR-345 and miR-132 associated with MMR deficiency in CRC regardless of geographic origin, and hypermethylation of miR-132 distinguished sporadic MMR-deficient CRC from Lynch-CRC. Finally, hypermethylation of miRNAs stratified 49 endometrial hyperplasias into low-methylator (simple hyperplasia) and high-methylator groups (complex hyperplasia with or without atypia) and suggested that miR-129-2 methylation in particular could serve as a marker of progression in early endometrial tumorigenesis.ConclusionsOur study identifies miR-345 and miR-132 as novel differentially methylated miRNAs in CRC, thereby facilitating sub-classification of CRC and links miR-129-2 methylation to early endometrial tumorigenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0059-3) contains supplementary material, which is available to authorized users.
Highlights
Altered expression of microRNAs commonly accompanies colorectal (CRC) and endometrial carcinoma (EC) development, but the underlying mechanisms and clinicopathological correlations remain to be clarified
Silenced miRNAs can be reactivated in cancer cell lines by treatment with the DNA methyltransferase inhibitor 5-aza-2′deoxycytidine (5-aza-CdR), often combined with a histone deacetylase inhibitor, and analogous drugs can be used for epigenetic cancer therapy in patients [9]
For analyses of clinical correlations, we evaluated possible associations of the Dm values for miR-129-2, 345, and 132 with gender, age, grade, stage, and sidedness among sporadic CRCs stratified by the mismatch repair (MMR) status
Summary
Altered expression of microRNAs (miRNAs) commonly accompanies colorectal (CRC) and endometrial carcinoma (EC) development, but the underlying mechanisms and clinicopathological correlations remain to be clarified. Treatment of cancer cell lines with demethylating agents revealed 109 significantly upregulated miRNAs. Seven met our stringent criteria for possible methylation-sensitive miRNAs and were used to screen patient specimens (205 CRCs and 36 ECs) by methylation-specific multiplex ligation-dependent probe amplification. Over half of miRNA promoters contain a CpG island as a possible target for aberrant methylation 6[6] which can lead to miRNA dysregulation. The CpG island is typically located in the proximal upstream region (20 kb of pre-miRNAs) for intronic miRNAs utilizing the host transcription start sites [6,7,8]. Silenced miRNAs can be reactivated in cancer cell lines by treatment with the DNA methyltransferase inhibitor 5-aza-2′deoxycytidine (5-aza-CdR), often combined with a histone deacetylase inhibitor (such as trichostatin A, TSA), and analogous drugs can be used for epigenetic cancer therapy in patients [9]
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