Advertisement

Competitive Endogenous RNA (ceRNA) Regulation Network of lncRNA–miRNA–mRNA in Colorectal Carcinogenesis

  • Jingwei Liu
  • Hao Li
  • Bowen Zheng
  • Liping Sun
  • Yuan YuanEmail author
  • Chengzhong XingEmail author
Original Article
  • 21 Downloads

Abstract

Background

Competitive endogenous RNA (ceRNA) regulation suggested complex network of all transcript RNAs including long noncoding RNAs (lncRNAs), which can act as natural miRNA sponges to inhibit miRNA functions and modulate mRNA expression. Until now, the specific ceRNA regulatory mechanism of lncRNA–miRNA–mRNA in colorectal cancer (CRC) still remains unclear.

Materials and Methods

RNA sequencing data of 478 colon adenocarcinoma cases and 41 controls as well as 166 rectum adenocarcinoma cases and 10 controls were obtained from The Cancer Genome Atlas (TCGA) to investigate the significant changes of lncRNAs, miRNAs and mRNAs in colorectal carcinogenesis. The target lncRNAs and mRNAs of miRNAs were predicted by miRWalk. Functional and enrichment analyses were conducted by DAVID database. The lncRNA–miRNA–mRNA interaction network was constructed using Cytoscape.

Results

We constructed ceRNA regulatory networks including 22 up-regulated lncRNAs, 12 down-regulated miRNAs and 122 up-regulated mRNAs, as well as 8 down-regulated lncRNAs, 43 up-regulated miRNAs and 139 down-regulated mRNAs. The GO enrichment showed that up-regulated genes mainly enriched in biological process including organic anion transport, collagen catabolic process, wound healing, Wnt receptor signalling and in pathways of tyrosine metabolism, taurine and hypotaurine metabolism, melanogenesis and phenylalanine metabolism. For down-regulated genes, significant enrichment was found in biological process of metal ion homeostasis, transmission of nerve impulse, cell–cell signalling, transmembrane transport and in pathways of ABC transporters, neuroactive ligand–receptor interaction, retinol metabolism, nitrogen metabolism and steroid hormone biosynthesis.

Conclusion

We identified significantly altered lncRNAs, miRNAs and mRNAs in colorectal carcinogenesis, which might serve as potential biomarkers for tumorigenesis of CRC. In addition, the ceRNA regulatory network of lncRNA–miRNA–mRNA was constructed, which would elucidate novel molecular mechanisms involved in initiation and progression of CRC, thus providing promising clues for clinical diagnosis and therapy.

Keywords

lncRNA miRNA ceRNA Colorectal cancer 

Notes

Funding

This study is supported by grants from Public Welfare Foundation of Liaoning Province (No. 2015005002).

Compliance with ethical standards

Conflict of interest

All of the authors declare that there is no conflict of interest.

Supplementary material

10620_2019_5506_MOESM1_ESM.docx (19 kb)
Supplementary material 1 (DOCX 19 kb)

References

  1. 1.
    Anastasiadou E, Jacob LS, Slack FJ. Non-coding RNA networks in cancer. Nat Rev Cancer. 2018;18:5–18.CrossRefGoogle Scholar
  2. 2.
    Esteller M, Pandolfi PP. The epitranscriptome of noncoding RNAs in Cancer. Cancer Discov. 2017;7:359–368.CrossRefGoogle Scholar
  3. 3.
    Bhan A, Soleimani M, Mandal SS. Long noncoding RNA and cancer: a new paradigm. Cancer Res. 2017;77:3965–3981.CrossRefGoogle Scholar
  4. 4.
    Bolha L, Ravnik-Glavac M, Glavac D. Long noncoding RNAs as biomarkers in cancer. Dis Mark. 2017;2017:7243968.Google Scholar
  5. 5.
    Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell. 2011;146:353–358.CrossRefGoogle Scholar
  6. 6.
    Giroud M, Scheideler M. Long non-coding RNAs in metabolic organs and energy homeostasis. Int J Mol Sci. 2017;18:2578.CrossRefGoogle Scholar
  7. 7.
    Hu X, Sood AK, Dang CV, Zhang L. The role of long noncoding RNAs in cancer: the dark matter matters. Curr Opin Genet Dev. 2017;48:8–15.CrossRefGoogle Scholar
  8. 8.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.CrossRefGoogle Scholar
  9. 9.
    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 GCR. 2007;1:20–27.Google Scholar
  10. 10.
    Li B, Shi C, Zhao J, Li B. Long noncoding RNA CCAT1 functions as a ceRNA to antagonize the effect of miR-410 on the down-regulation of ITPKB in human HCT-116 and HCT-8 cells. Oncotarget. 2017;8:92855–92863.Google Scholar
  11. 11.
    Chen DL, Lu YX, Zhang JX, et al. Long non-coding RNA UICLM promotes colorectal cancer liver metastasis by acting as a ceRNA for microRNA-215 to regulate ZEB2 expression. Theranostics. 2017;7:4836–4849.CrossRefGoogle Scholar
  12. 12.
    Xu J, Zhang R, Zhao J. The novel long noncoding RNA TUSC7 inhibits proliferation by sponging MiR-211 in colorectal cancer. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol. 2017;41:635–644.CrossRefGoogle Scholar
  13. 13.
    Zhou XG, Huang XL, Liang SY, et al. Identifying miRNA and gene modules of colon cancer associated with pathological stage by weighted gene co-expression network analysis. OncoTargets Ther. 2018;11:2815–2830.CrossRefGoogle Scholar
  14. 14.
    Wei HT, Guo EN, Liao XW, et al. Genomescale analysis to identify potential prognostic microRNA biomarkers for predicting overall survival in patients with colon adenocarcinoma. Oncol Rep. 2018;40:1947–1958.Google Scholar
  15. 15.
    Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.CrossRefGoogle Scholar
  16. 16.
    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
  17. 17.
    Dweep H, Gretz N, Sticht C. miRWalk database for miRNA–target interactions. Methods Mol Biol (Clifton NJ). 2014;1182:289–305.CrossRefGoogle Scholar
  18. 18.
    Dennis G Jr, Sherman BT, Hosack DA, et al. DAVID: database for annotation, visualization, and integrated discovery. Genome Biol. 2003;4:P3.CrossRefGoogle Scholar
  19. 19.
    The Gene Ontology (GO) project in 2006. Nucleic Acids Research. 2006;34:D322–326.Google Scholar
  20. 20.
    Kanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28:27–30.CrossRefGoogle Scholar
  21. 21.
    Lin C, Yang L. Long noncoding RNA in cancer: wiring signaling circuitry. Trends Cell Biol. 2017;28:287–301.CrossRefGoogle Scholar
  22. 22.
    Renganathan A, Felley-Bosco E. Long noncoding RNAs in cancer and therapeutic potential. Adv Exp Med Biol. 2017;1008:199–222.CrossRefGoogle Scholar
  23. 23.
    Slaby O, Laga R, Sedlacek O. Therapeutic targeting of non-coding RNAs in cancer. Biochem J. 2017;474:4219–4251.CrossRefGoogle Scholar
  24. 24.
    Sun W, Yang Y, Xu C, Guo J. Regulatory mechanisms of long noncoding RNAs on gene expression in cancers. Cancer Genet. 2017;216–217:105–110.CrossRefGoogle Scholar
  25. 25.
    Zhang J, Jiang Y, Zhu J, et al. Overexpression of long non-coding RNA colon cancer-associated transcript 2 is associated with advanced tumor progression and poor prognosis in patients with colorectal cancer. Oncol Lett. 2017;14:6907–6914.Google Scholar
  26. 26.
    Ling H, Spizzo R, Atlasi Y, et al. CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Res. 2013;23:1446–1461.CrossRefGoogle Scholar
  27. 27.
    Han Y, Yang YN, Yuan HH, et al. UCA1, a long non-coding RNA up-regulated in colorectal cancer influences cell proliferation, apoptosis and cell cycle distribution. Pathology. 2014;46:396–401.CrossRefGoogle Scholar
  28. 28.
    Ni B, Yu X, Guo X, et al. Increased urothelial cancer associated 1 is associated with tumor proliferation and metastasis and predicts poor prognosis in colorectal cancer. Int J Oncol. 2015;47:1329–1338.CrossRefGoogle Scholar
  29. 29.
    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
  30. 30.
    Mima K, Nishihara R, Yang J, et al. MicroRNA MIR21 (miR-21) and PTGS2 expression in colorectal cancer and patient survival. Clin Cancer Res. 2016;22:3841–3848.CrossRefGoogle Scholar
  31. 31.
    Ding M, Zhang T, Li S, Zhang Y, Qiu Y, Zhang B. Correlation analysis between liver metastasis and serum levels of miR200 and miR141 in patients with colorectal cancer. Mol Med Rep. 2017;16:7791–7795.CrossRefGoogle Scholar
  32. 32.
    Amado NG, Predes D, Moreno MM, Carvalho IO, Mendes FA, Abreu JG. Flavonoids and Wnt/beta-catenin signaling: potential role in colorectal cancer therapies. Int J Mol Sci. 2014;15:12094–12106.CrossRefGoogle Scholar
  33. 33.
    Masuda M, Sawa M, Yamada T. Therapeutic targets in the Wnt signaling pathway: feasibility of targeting TNIK in colorectal cancer. Pharmacol Ther. 2015;156:1–9.CrossRefGoogle Scholar
  34. 34.
    Xue X, Taylor M, Anderson E, et al. Hypoxia-inducible factor-2alpha activation promotes colorectal cancer progression by dysregulating iron homeostasis. Cancer Res. 2012;72:2285–2293.CrossRefGoogle Scholar
  35. 35.
    Matsumura T, Sugimachi K, Iinuma H, et al. Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer. Br J Cancer. 2015;113:275–281.CrossRefGoogle Scholar
  36. 36.
    Wang X, Ding X, Nan L, et al. Investigation of the roles of exosomes in colorectal cancer liver metastasis. Oncol Rep. 2015;33:2445–2453.CrossRefGoogle Scholar
  37. 37.
    Carethers JM, Jung BH. Genetics and genetic biomarkers in sporadic colorectal cancer. Gastroenterology. 2015;149:1177–1190 e1173.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 Surgery, the First Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University)Liaoning Provincial Education DepartmentShenyang CityChina

Personalised recommendations