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Epigenetic Alternations of MicroRNAs and DNA Methylation Contribute to Liver Metastasis of Colorectal Cancer

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Abstract

Background

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.

Results

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.

Conclusion

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.

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Abbreviations

CRC:

Colorectal cancer

DEG:

Differentially expressed gene

DMG:

Differentially methylated gene

DEMs:

Differentially expressed miRNAs

EMT:

Epithelial-to-mesenchymal transition

GEO:

Gene Expression Omnibus

GO:

Gene ontology

KEGG:

Kyoto encyclopedia of genes and genomes

PPI:

Protein–protein interaction

STRING:

Search tool for the retrieval of interacting genes

NCBI:

The National Center for Biotechnology Information

BP:

Biological processes

MF:

Molecular function

CC:

Cell component

CLM:

Colorectal liver metastasis

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Acknowledgment

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.

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Authors and Affiliations

  1. Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, 155# North Nanjing Street, Heping District, Shenyang City, 110001, Liaoning Province, China

    Jingwei Liu, Hao Li, Liping Sun, Shixuan Shen, Quan Zhou, Yuan Yuan & Chengzhong Xing

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  1. Jingwei Liu
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  2. Hao Li
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  3. Liping Sun
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  6. Yuan Yuan
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  7. Chengzhong Xing
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Contributions

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.

Corresponding authors

Correspondence to Yuan Yuan or Chengzhong Xing.

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All authors declare that there is no conflict of interest.

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Liu, J., Li, H., Sun, L. et al. Epigenetic Alternations of MicroRNAs and DNA Methylation Contribute to Liver Metastasis of Colorectal Cancer. Dig Dis Sci 64, 1523–1534 (2019). https://doi.org/10.1007/s10620-018-5424-6

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  • DOI: https://doi.org/10.1007/s10620-018-5424-6

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