Identification of subgroup-specific miRNA patterns by epigenetic profiling of sporadic and Lynch syndrome-associated colorectal and endometrial carcinoma

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.

LncRNA SNHG5 affects cell proliferation, metastasis and migration of colorectal cancer through regulating miR-132-3p/CREB5

“…12 Both downregulation of tumor suppressive miRNAs targeting proto-oncogenes and upregulation of oncogenic miRNAs targeting tumor suppressor genes can lead to the tumorigenesis and tumor progression. 13 MiR-132, which has been vigorously studied, is located in chromosome 17p13.3. As a possible target of SNHG5, it has exhibited correlation with various kinds of malignancies including glioma, 14 CRC, 15 breast cancer, 16 prostate cancer and pancreatic cancer.…”

Epigenetic silencing of miR-181b contributes to tumorigenicity in colorectal cancer by targeting RASSF1A

“…It is commonly accepted that microRNAs can contribute to global epigenetic regulation in CRC (23)(24)(25). For example, miR-143 is found to be a tumor suppressor which directly targets DNA methyltransferase 3A (DNMT3A) and leads to decreased DNMT3A in CRC tissues (26).…”

Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer

“…Not only miRNA regulates gene expression in an epigenetic way but also miRNA expressions may be regulated epigenetically. With containing a CpG island in the promoter region, most of the miRNAs are favorable for aberrant methylation which can give rise to dysregulation of miRNA [49,50] . Kaur et al [49] identified a correlation between miR-345 and miR-132 hypermethylation and MMR deficiency ( Table 1).…”

“…This study revealed that SEMA4A (V78M) lead to activation of MAPK/Erk and PI3K/Akt signaling. Moreover, SEMA4A mutations, c.1451G > C and c.977C > T and the single-nucleotide polymorphism c.2044C [46] MSI Earle et al [48] miR-26b Down MSS Earle et al [48] miR-31 Up MSI Earle et al [48] miR-223 Up MSI Earle et al [48] miR-486-5p Down MSI Balaguer et al [47] miR-622 Up MSI Balaguer et al [47] miR-1238 Up MSI Balaguer et al [47] miR-1362-5p Down MSI Balaguer et al [47] miR-132 Down MMR deficiency Kaur et al [49] miR-345 Down MMR deficiency Kaur et al [49] with extra-intestinal manifestations in a study of 411 FAP patients. Recent studies demonstrated the enrichment of pyloric gland adenomas of the stomach, in addition to fundic gland polyps and foveolar-type adenomas in patients with FAP [75,76] .…”

“…Earle et al [48] described the different expression profile of miR-223, miR-155, and miR-92 between MSI and MSS CRCs. So far, Kaur et al [49] have investigated the association of miR-132 methylation and sporadic MSI CRC tumors located in the proximal colon in a comparative study of Finnish and Australian population. In addition, different from MSS tumors, hypermethylation of miR-345 had a significant association with sporadic MSI in Finnish CRCs [49] .…”