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Tumor Biology

, Volume 36, Issue 5, pp 3129–3136 | Cite as

Oncocers: ceRNA-mediated cross-talk by sponging miRNAs in oncogenic pathways

  • Sercan Ergun
  • Serdar Oztuzcu
Review

Abstract

Competing endogenous RNAs (ceRNAs) are RNA transcripts which can communicate with each other by decreasing targeting concentration of micro-RNA (miRNA) with the derepression of other messenger RNAs (mRNAs) having the common miRNA response elements (MREs). Oncocers are ceRNAs taking crucial roles in oncogenic pathways processed in many types of cancer, and this study analyzes oncocer-mediated cross-talk by sponging microRNAs (miRNAs) in these pathways. While doing this, breast, liver, colon, prostate, gastric, lung, endometrium, thyroid and epithelial cancers and melanoma, rhabdomyosarcoma, glioblastoma, acute promyelocytic leukemia, retinoblastoma, and neuroblastoma were analyzed with respect to ceRNA-based carcinogenesis. This study defines, firstly, oncocers in the literature and contains all oncocer-related findings found up to now. Therefore, it will help to increase our comprehension about oncocer-mediated mechanisms. Via this study, a novel perspective would be produced to make clear cancer mechanisms and suggest novel approaches to regulate ceRNA networks via miRNA competition for cancer therapeutics.

Graphical Abstract

Multiple RNA transcripts have common MREs for the similar miRNA in their 3′-untranslated regions (3′-UTRs). Upregulation of ceRNAs rises the abundance of specific MREs and shifts the miRNA pool distribution, as a result, leading to the increased expression of target mRNA. The depot of genomic mutations and epigenetic alterations changing gene function and expression causes cancers. Herewith, genome-based somatic base-pair mutations, DNA copy number alterations, chromosomal translocation, also transcript fusions, alternative splicing are usually seen in cancer situations. Consequently, such cases causing changed UTR expression in transcripts influence the levels of MRE or present new MREs into the cells. Alterations in MREs of ceRNAs affect the capability of a specific mRNA transcript to attach or titrate miRNAs. As a result, the disturbed ceRNA network can lead to diseases and cancers. As a new term in RNA world, oncocers—the name for ceRNAs taking crucial roles in oncogenic pathways—are processed in many types of cancer, and oncocer-mediated cross-talk are analyzed by sponging miRNAs in these pathways.

Keywords

Oncocer ceRNA miRNA lncRNA Cancer 

Abbreviations

3′-UTR

3′-Untranslated region

ARM

Alveolar rhabdomyosarcoma

ATXN3

Ataxin 3

ceRNA

Competing endogenous RNA

ceRNET

ceRNA network

EMT

Epithelial-to-mesenchymal transition

ERM

Embryonic rhabdomyosarcoma

ET

Endometrial tumorspheres

FGFR4

Fibroblast growth factor receptor 4

HDACi

Histone deacetylase inhibitors

HULC

Highly upregulated in liver cancer

IGFR1

Insulin like growth factor 1 receptor

lncRNA

Long noncoding RNAs

miRNA

Micro RNA

MRE

MiRNA response element

ncRNA

Noncoding RNA

PTCSC3

Papillary thyroid carcinoma susceptibility candidate 3

ZEB

Zinc finger E-box-binding homeobox

Notes

Conflicts of interest

None

References

  1. 1.
    Kataoka M, Wang D-Z. Non-coding RNAs including miRNAs and lncRNAs in cardiovascular biology and disease. Cells. 2014;3:883–98.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Kameswaran V, Kaestner KH. The missing lnc (RNA) between the pancreatic β-cell and diabetes. Front Genet. 2014;5:200.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69.CrossRefPubMedGoogle Scholar
  5. 5.
    Tan J, Marques A. The miRNA-mediated cross-talk between transcripts provides a novel layer of posttranscriptional regulation. Adv Genet. 2013;85:149–99.Google Scholar
  6. 6.
    Ergun S, Arman K, Temiz E, Bozgeyik İ, Yumrutaş Ö, et al. Expression patterns of miR-221 and its target caspase-3 in different cancer cell lines. Mol Biol Rep. 2014;41:5877–81.CrossRefPubMedGoogle Scholar
  7. 7.
    Arman K, Ergün S, Temiz E, Öztuzcu S. The interrelationship between HER2 and CASP3/8 with apoptosis in different cancer cell lines. Mol Biol Rep. 2014;41(12):1–6.CrossRefGoogle Scholar
  8. 8.
    Ergün S, Ulasli M, Igci Y, Igci M, Kırkbes S, et al. The association of the expression of miR-122-5p and its target ADAM10 with human breast cancer. Mol Biol Rep. 2015;42:497–505.CrossRefPubMedGoogle Scholar
  9. 9.
    Costa V, Esposito R, Aprile M, Ciccodicola A. Non-coding RNA and pseudogenes in neurodegenerative diseases:“the (un) usual suspects”. Front Genet. 2012;3:231.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ergün S, Öztuzcu S (2014) MiR-221: a critical player in apoptosis as a target of caspase-3. Cancer Cell Microenviron 1:10–14800/ccm. 14313.Google Scholar
  11. 11.
    Sümbül AT, Göğebakan B, Ergün S, Yengil E, Batmacı CY, Yaldız M, Sezer A, Aldemir Ö, Özyılkan Ö. miR-204-5p expression in colorectal cancer: an autophagy-associated gene. Tumor Biol. 2014;35(12):12713–9.Google Scholar
  12. 12.
    Ergun S, Oztuzcu S. Computational analysis of 3′ UTR Region of CASP3 with respect to miRSNPs and SNPs in targetting miRNAs. Comput Biol Chem. 2014;53PB:235–41.CrossRefPubMedGoogle Scholar
  13. 13.
    Eades G, Zhang Y-S, Li Q-L, Xia J-X, Yao Y, et al. Long non-coding RNAs in stem cells and cancer. World J Clin Oncol. 2014;5:134.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Rossi MN, Antonangeli F. LncRNAs: new players in apoptosis control. Int J Cell Biol. 2014;2014, 473857.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Serviss JT, Johnsson P, Grandér D. An emerging role for long non-coding RNAs in cancer metastasis. Front Genet. 2014;5:234.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Khvorova A, Wolfson A. New competition in RNA regulation. Nat Biotechnol. 2012;30:58–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell. 2011;146:353–8.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ala U, Karreth FA, Bosia C, Pagnani A, Taulli R, et al. Integrated transcriptional and competitive endogenous RNA networks are cross-regulated in permissive molecular environments. Proc Natl Acad Sci. 2013;110:7154–9.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kalyana-Sundaram S, Kumar-Sinha C, Shankar S, Robinson DR, Wu Y-M, et al. Expressed pseudogenes in the transcriptional landscape of human cancers. Cell. 2012;149:1622–34.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Li L, Wang D, Xue M, Mi X, Liang Y, Wang P. 3′ UTR shortening identifies high-risk cancers with targeted dysregulation of the ceRNA network. Sci Rep. 2014;4:5406.Google Scholar
  21. 21.
    Karreth FA, Pandolfi PP. ceRNA cross-talk in cancer: when ce-bling rivalries go awry. Cancer Discov. 2013;3:1113–21.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kartha RV, Subramanian S. Competing endogenous RNAs (ceRNAs): new entrants to the intricacies of gene regulation. Front Genet. 2014;5:8.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Sarver AL, Subramanian S. Competing endogenous RNA database. Bioinformation. 2012;8:731.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Karreth FA, Ala U, Provero P, Pandolfi PP (2014) Pseudogenes as competitive endogenous RNAs: target prediction and validation. Pseudogenes. Springer. pp. 199–212.Google Scholar
  25. 25.
    Cesana M, Daley GQ. Deciphering the rules of ceRNA networks. Proc Natl Acad Sci. 2013;110:7112–3.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Yang J, Li T, Gao C, Lv X, Liu K, et al. FOXO1 3′ UTR functions as a ceRNA in repressing the metastases of breast cancer cells via regulating miRNA activity. FEBS Lett. 2014;588:3218–24.CrossRefPubMedGoogle Scholar
  27. 27.
    Sen R, Ghosal S, Das S, Balti S, Chakrabarti J. Competing endogenous RNA: the key to posttranscriptional regulation. Sci World J. 2014;2014, 896206.CrossRefGoogle Scholar
  28. 28.
    Giza DE, Vasilescu C, Calin GA. MicroRNAs and ceRNAs: therapeutic implications of RNA networks. Expert Opin Biol Ther. 2014;14:1285–93.CrossRefPubMedGoogle Scholar
  29. 29.
    Su X, Xing J, Wang Z, Chen L, Cui M, et al. microRNAs and ceRNAs: RNA networks in pathogenesis of cancer. Chin J Cancer Res. 2013;25:235.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Karreth FA, Tay Y, Perna D, Ala U, Tan SM, et al. In vivo identification of tumor-suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma. Cell. 2011;147:382–95.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Berger MF, Levin JZ, Vijayendran K, Sivachenko A, Adiconis X, et al. Integrative analysis of the melanoma transcriptome. Genome Res. 2010;20:413–27.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Tay Y, Kats L, Salmena L, Weiss D, Tan SM, et al. Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell. 2011;147:344–57.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Sumazin P, Yang X, Chiu H-S, Chung W-J, Iyer A, et al. An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma. Cell. 2011;147:370–81.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell. 2011;147:358–69.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Nie L, Wu H-J, Hsu J-M, Chang S-S, LaBaff AM, et al. Long non-coding RNAs: versatile master regulators of gene expression and crucial players in cancer. Am J Transl Res. 2012;4:127.PubMedPubMedCentralGoogle Scholar
  36. 36.
    de Giorgio A, Krell J, Harding V, Stebbing J, Castellano L. Emerging roles of competing endogenous RNAs in cancer: insights from the regulation of PTEN. Mol Cell Biol. 2013;33:3976–82.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zhou X, Liu J, Wang W. Construction and investigation of breast-cancer-specific ceRNA network based on the mRNA and miRNA expression data. IET Syst Biol. 2014;8(3):96–103.CrossRefPubMedGoogle Scholar
  38. 38.
    Ferracin M, Bassi C, Pedriali M, Pagotto S, D’Abundo L, et al. miR-125b targets erythropoietin and its receptor and their expression correlates with metastatic potential and ERBB2/HER2 expression. Mol Cancer. 2013;12:130.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Paci P, Colombo T, Farina L. Computational analysis identifies a sponge interaction network between long non-coding RNAs and messenger RNAs in human breast cancer. BMC Syst Biol. 2014;8:83.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Hou P, Zhao Y, Li Z, Yao R, Ma M, et al. LincRNA-ROR induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis. Cell Death Dis. 2014;5:e1287.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Cha YH, Kim NH, Park C, Lee I, Kim HS, et al. MiRNA-34 intrinsically links p53 tumor suppressor and Wnt signaling. Cell Cycle. 2012;11:1273–81.CrossRefPubMedGoogle Scholar
  42. 42.
    Fang L, Du WW, Yang X, Chen K, Ghanekar A, et al. Versican 3′-untranslated region (3′-UTR) functions as a ceRNA in inducing the development of hepatocellular carcinoma by regulating miRNA activity. FASEB J. 2013;27:907–19.CrossRefPubMedGoogle Scholar
  43. 43.
    Zhao L, Li F, Taylor EW. Can tobacco use promote HCV-induced miR-122 hijacking and hepatocarcinogenesis? Med Hypotheses. 2013;80:131–3.CrossRefPubMedGoogle Scholar
  44. 44.
    Pilyugin M, Irminger-Finger I. Long non-coding RNA and microRNAs might act in regulating the expression of BARD1 mRNAs. Int J Biochem Cell Biol. 2014;54:356–67.CrossRefPubMedGoogle Scholar
  45. 45.
    Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, et al. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature. 2010;465:1033–8.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Shen K, Mao R, Ma L, Li Y, Qiu Y, et al. Post‐transcriptional regulation of the tumor suppressor miR‐139‐5p and a network of miR‐139‐5p‐mediated mRNA interactions in colorectal cancer. FEBS J. 2014;281:3609–24.CrossRefPubMedGoogle Scholar
  47. 47.
    Gao X, Fu C, Lao X, Tan Z. Competing endogenous RNA regulation mechanism and its role in the development and progression of colorectal cancer. Chin J Gastrointest Surg. 2012;15:1318–21.Google Scholar
  48. 48.
    Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014;505:344–52.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Liu X-h, Sun M, Nie F-q, Ge Y-b, Zhang E-b, et al. lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Mol Cancer. 2014;13:92.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Xia T, Liao Q, Jiang X, Shao Y, Xiao B, et al. Long noncoding RNA associated-competing endogenous RNAs in gastric cancer. Sci Rep. 2014;4:6088. doi: 10.1038/srep06088.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Tay Y, Karreth FA, Pandolfi PP. Aberrant ceRNA activity drives lung cancer. Cell Res. 2014;24(3):259–60.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Kumar MS, Armenteros-Monterroso E, East P, Chakravorty P, Matthews N, et al. HMGA2 functions as a competing endogenous RNA to promote lung cancer progression. Nature. 2014;505(7482):212–7.CrossRefPubMedGoogle Scholar
  53. 53.
    Sacco J, Yau T, Darling S, Patel V, Liu H, et al. The deubiquitylase ataxin-3 restricts PTEN transcription in lung cancer cells. Oncogene. 2014;33(33):4265–72.CrossRefPubMedGoogle Scholar
  54. 54.
    Zhou X, Gao Q, Wang J, Zhang X, Liu K, et al. Linc-RNA-RoR acts as a “sponge” against mediation of the differentiation of endometrial cancer stem cells by microRNA-145. Gynecol Oncol. 2014;133:333–9.CrossRefPubMedGoogle Scholar
  55. 55.
    Kovalenko T, Sorokina A, Ozolinya L, Patrushev L. Methylation of the pseudogene PTENP1 5′-terminal region in endometrial cancer and hyperplasia. Russ J Bioorg Chem. 2013;39:397–405.CrossRefGoogle Scholar
  56. 56.
    Fan M, Li X, Jiang W, Huang Y, Li J, et al. A long non-coding RNA, PTCSC3, as a tumor suppressor and a target of miRNAs in thyroid cancer cells. Exp Ther Med. 2013;5:1143–6.PubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Ulubey Vocational Higher SchoolOrdu UniversityOrduTurkey
  2. 2.Department of Medical Biology, Faculty of MedicineGaziantep UniversityGaziantepTurkey

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