Digestive Diseases and Sciences

, Volume 64, Issue 6, pp 1523–1534 | Cite as

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

  • Jingwei Liu
  • Hao Li
  • Liping Sun
  • Shixuan Shen
  • Quan Zhou
  • Yuan YuanEmail author
  • Chengzhong XingEmail author
Original Article



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.


Epigenetics MicroRNA DNA methylation Colorectal cancer 



Colorectal cancer


Differentially expressed gene


Differentially methylated gene


Differentially expressed miRNAs


Epithelial-to-mesenchymal transition


Gene Expression Omnibus


Gene ontology


Kyoto encyclopedia of genes and genomes


Protein–protein interaction


Search tool for the retrieval of interacting genes


The National Center for Biotechnology Information


Biological processes


Molecular function


Cell component


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.

Author’s contribution

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.

Supplementary material

10620_2018_5424_MOESM1_ESM.jpg (189 kb)
Supplementary material 1 (JPEG 189 kb)


  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.CrossRefGoogle Scholar
  2. 2.
    Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62:220–241.CrossRefGoogle Scholar
  3. 3.
    Donadon M, Ribero D, Morris-Stiff G, Abdalla EK, Vauthey JN. New paradigm in the management of liver-only metastases from colorectal cancer. Gastrointest Cancer Res. 2007;1:20–27.Google Scholar
  4. 4.
    Garden OJ, Rees M, Poston GJ, et al. Guidelines for resection of colorectal cancer liver metastases. Gut. 2006;55:iii1–iii8.CrossRefGoogle Scholar
  5. 5.
    Pawlik TM, Choti MA. Surgical therapy for colorectal metastases to the liver. J Gastrointest Surg. 2007;11:1057–1077.CrossRefGoogle Scholar
  6. 6.
    Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science. 2017;357:6348.CrossRefGoogle Scholar
  7. 7.
    Dawson MA. The cancer epigenome: Concepts, challenges, and therapeutic opportunities. Science. 2017;355:1147–1152.CrossRefGoogle Scholar
  8. 8.
    Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16:203–222.CrossRefGoogle Scholar
  9. 9.
    Rupaimoole R, Calin GA, Lopez-Berestein G, Sood AK. miRNA deregulation in cancer cells and the tumor microenvironment. Cancer Discov. 2016;6:235–246.CrossRefGoogle Scholar
  10. 10.
    Hur K, Toiyama Y, Okugawa Y, et al. Circulating microRNA-203 predicts prognosis and metastasis in human colorectal cancer. Gut. 2017;66:654–665.CrossRefGoogle Scholar
  11. 11.
    Zhang JX, Mai SJ, Huang XX, et al. MiR-29c mediates epithelial-to-mesenchymal transition in human colorectal carcinoma metastasis via PTP4A and GNA13 regulation of beta-catenin signaling. Ann Oncol. 2014;25:2196–2204.CrossRefGoogle Scholar
  12. 12.
    Chen DL, Wang ZQ, Zeng ZL, et al. Identification of microRNA-214 as a negative regulator of colorectal cancer liver metastasis by way of regulation of fibroblast growth factor receptor 1 expression. Hepatology. 2014;60:598–609.CrossRefGoogle Scholar
  13. 13.
    Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016;17:630–641.CrossRefGoogle Scholar
  14. 14.
    Kim M, Costello J. DNA methylation: an epigenetic mark of cellular memory. Exp Mol Med. 2017;49:e322.CrossRefGoogle Scholar
  15. 15.
    Kelly AD, Issa JJ. The promise of epigenetic therapy: reprogramming the cancer epigenome. Curr Opin Genet Dev. 2017;42:68–77.CrossRefGoogle Scholar
  16. 16.
    Hur K, Cejas P, Feliu J, et al. Hypomethylation of long interspersed nuclear element-1 (LINE-1) leads to activation of proto-oncogenes in human colorectal cancer metastasis. Gut. 2014;63:635–646.CrossRefGoogle Scholar
  17. 17.
    Ebert MP, Mooney SH, Tonnes-Priddy L, et al. Hypermethylation of the TPEF/HPP1 gene in primary and metastatic colorectal cancers. Neoplasia. 2005;7:771–778.CrossRefGoogle Scholar
  18. 18.
    Dweep H, Sticht C, Pandey P, Gretz N. miRWalk–database: prediction of possible miRNA binding sites by “walking” the genes of three genomes. J Biomed Inform. 2011;44:839–847.CrossRefGoogle Scholar
  19. 19.
    Dweep H, Gretz N, Sticht C. miRWalk database for miRNA-target interactions. Methods Mol Biol. 2014;1182:289–305.CrossRefGoogle Scholar
  20. 20.
    Dennis G Jr, Sherman BT, Hosack DA, et al. DAVID: database for annotation, visualization, and integrated discovery. Genome Biol. 2003;4:P3.CrossRefGoogle Scholar
  21. 21.
    The Gene Ontology Consortium. The Gene Ontology (GO) project in 2006. Nucleic Acids Research. 2006;34:D322–D326.CrossRefGoogle Scholar
  22. 22.
    Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28:27–30.CrossRefGoogle Scholar
  23. 23.
    Derosa G, Sahebkar A, Maffioli P. The role of various peroxisome proliferator-activated receptors and their ligands in clinical practice. J Cell Physiol. 2018;233:153–161.CrossRefGoogle Scholar
  24. 24.
    Matera AG, Wang Z. A day in the life of the spliceosome. Nat Rev Mol Cell Biol. 2014;15:108–121.CrossRefGoogle Scholar
  25. 25.
    Carethers JM, Jung BH. Genetics and genetic biomarkers in sporadic colorectal cancer. Gastroenterology. 2015;149:1177–1190.e1173.CrossRefGoogle Scholar
  26. 26.
    Budi EH, Duan D, Derynck R. Transforming growth factor-beta receptors and smads: regulatory complexity and functional versatility. Trends Cell Biol. 2017;27:658–672.CrossRefGoogle Scholar
  27. 27.
    Nusse R, Clevers H. Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169:985–999.CrossRefGoogle Scholar
  28. 28.
    Onstenk W, Sieuwerts AM, Mostert B, et al. Molecular characteristics of circulating tumor cells resemble the liver metastasis more closely than the primary tumor in metastatic colorectal cancer. Oncotarget. 2016;7:59058–59069.CrossRefGoogle Scholar
  29. 29.
    Lupp A, Klenk C, Rocken C, Evert M, Mawrin C, Schulz S. Immunohistochemical identification of the PTHR1 parathyroid hormone receptor in normal and neoplastic human tissues. Eur J Endocrinol. 2010;162:979–986.CrossRefGoogle Scholar
  30. 30.
    Teraoku H, Morine Y, Ikemoto T, et al. Role of thrombospondin-1 expression in colorectal liver metastasis and its molecular mechanism. J Hepatobiliary Pancreat Sci. 2016;23:565–573.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Tumor Etiology and Screening Department of Cancer Institute and General SurgeryThe First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education DepartmentShenyang CityChina

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