Abstract
Simple SummaryChanges in the expression of key molecules such as microRNAs (miRs) can drive or suppress carcinogenesis and metastasis. A number of established transcriptional and genetic mechanisms regulate miR gene expression, but methylation/epigenetics have been analyzed less. Here, we systematically evaluated genome-wide methylation changes, focusing on miR, downstream targets, and further genes relevant for metastasis in colorectal cancers (CRC), including CpG islands, open seas, and north and south shore regions. A number of miRs deregulated during CRC progression/metastasis were significantly affected by methylation changes, especially within CpG islands and open seas. Several of these miRs cooperate in cancer- and metastasis-related pathways, while methylation changes otherwise primarily affect protein-coding genes. Our results highlight alternative routes to the transcriptional and genetic control of miR and further gene expression relevant for CRC progression and metastasis by changes in gene methylation. They also bear important therapeutic implications since drugs that alter methylation states are now in clinical use.MiRs are important players in cancer and primarily genetic/transcriptional means of regulating their gene expression are known. However, epigenetic changes modify gene expression significantly. Here, we evaluated genome-wide methylation changes focusing on miR genes from primary CRC and corresponding normal tissues. Differentially methylated CpGs spanning CpG islands, open seas, and north and south shore regions were evaluated, with the largest number of changes observed within open seas and islands. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed several of these miRs to act in important cancer-related pathways, including phosphatidylinositol 3-kinase (PI3K)–protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) pathways. We found 18 miR genes to be significantly differentially methylated, with MIR124-2, MIR124-3, MIR129-2, MIR137, MIR34B, MIR34C, MIR548G, MIR762, and MIR9-3 hypermethylated and MIR1204, MIR17, MIR17HG, MIR18A, MIR19A, MIR19B1, MIR20A, MIR548F5, and MIR548I4 hypomethylated in CRC tumor compared with normal tissue, most of these miRs having been shown to regulate steps of metastasis. Generally, methylation changes were distributed evenly across all chromosomes with predominance for chromosomes 1/2 and protein-coding genes. Interestingly, chromosomes abundantly affected by methylation changes globally were rarely affected by methylation changes within miR genes. Our findings support additional mechanisms of methylation changes affecting (miR) genes that orchestrate CRC progression and metastasis.
Highlights
contribute to diverse aspects of (CRC) is presently the second leading cause of cancer deaths and third most commonly diagnosed cancer worldwide [1]
In this study of colorectal carcinomas, we explored genome-wide methylation changes, focusing on miRs genes due to the important role they play in cancer progression and metastasis
It is an established notion that the miRs we found as significantly changed in the methylation of their genes in colorectal carcinomas, as opposed to normal tissues, are highly relevant molecules that contribute to diverse aspects of (CRC) carcinogenesis, tumor progression, and metastasis
Summary
CRC is presently the second leading cause of cancer deaths and third most commonly diagnosed cancer worldwide [1]. The successive acquisition of genetic and epigenetic alterations has been shown to drive the initiation and progression of adenomas to carcinomas in CRC. These mediate the transformation of a normal colorectal epithelium to a benign adenoma, and the accumulation of further multiple genetic and epigenetic changes in particular clones can result in an invasive and metastatic phenotype [3,4,5]. A multitude of research efforts have sought to identify and investigate the key molecules involved in the initiation and progression of CRC. A large number of molecular drivers have been identified, of which molecules such as adenomatous polyposis coli (APC), tumor protein P53 (TP53), kirsten rat sarcoma virus (KRAS), and catenin beta-1 (CTNNB1) appear to play crucial roles [4]
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