Epigenetic Alternations of MicroRNAs and DNA Methylation Contribute to Liver Metastasis of Colorectal Cancer
Liver metastasis is a major cause of mortality in colorectal cancer (CRC). Epigenetic alternations could serve as biomarkers for cancer diagnosis and prognosis. In this study, we analyzed microarray data in order to identify core genes and pathways which contribute to liver metastasis in CRC under epigenetic regulations.
Materials and Methods
Data of miRNAs (GSE35834, GSE81582), DNA methylation (GSE90709, GSE77955), and mRNA microarrays (GSE68468, GSE81558) were downloaded from GEO database. Differentially expressed genes (DEGs), differentially expressed miRNAs (DEMs), and differentially methylated genes (DMGs) were obtained by GEO2R. The target genes of DEMs were predicted by miRWalk. Functional and enrichment analyses were conducted by DAVID database. Protein–protein interaction (PPI) network was constructed in STRING and visualized using Cytoscape.
In liver metastasis, miR-143-3p, miR-10b-5p, miR-21-5p, and miR-518f-5p were down-regulated, while miR-122-5p, miR-885-5p, miR-210-3p, miR-130b-5p, miR-1275, miR-139-5p, miR-139-3p, and miR-1290 were up-regulated compared with primary CRC. DEGs targeted by altered miRNAs were enriched in pathways including complement, PPAR signaling, ECM–receptor interaction, spliceosome, and focal adhesion. In addition, aberrant DNA methylation-regulated genes showed enrichment in pathways of amino acid metabolism, calcium signaling, TGF-beta signaling, cell cycle, spliceosome, and Wnt signaling.
Our study identified a series of differentially expressed genes which are associated with epigenetic alternations of miRNAs and DNA methylation in colorectal liver metastasis. Up-regulated genes of SLC10A1, MAPT, SHANK2, PTH1R, and C2, as well as down-regulated genes of CAB39, CFLAR, CTSC, THBS1, and TRAPPC3 were associated with both miRNA and DNA methylation, which might become promising biomarker of colorectal liver metastasis in future.
KeywordsEpigenetics MicroRNA DNA methylation Colorectal cancer
Differentially expressed gene
Differentially methylated gene
Differentially expressed miRNAs
Gene Expression Omnibus
Kyoto encyclopedia of genes and genomes
Search tool for the retrieval of interacting genes
The National Center for Biotechnology Information
Colorectal liver metastasis
This study is supported by Grants from Public Welfare Foundation of Liaoning Province (No. 2015005002), Fund for Scientific Research of The First Hospital of China Medical University (FHCMU-FSR), and the National Science and Technology Support Program (2015BAI13B07).
Availability of data and materials
The authors declare that the data supporting the findings of this study are available within the article.
LJW, SLP, SSX, and ZQ participated in the statistical analysis and wrote the manuscript. LJW and LH downloaded and processed the raw data. YY and XCZ conceived the study, participated in its design and coordination, and helped to draft the manuscript. All authors read and approved the final manuscript.
Compliance with ethical standards
Conflict of interest
All authors declare that there is no conflict of interest.