Advertisement

Unearthing Regulatory Axes of Breast Cancer circRNAs Networks to Find Novel Targets and Fathom Pivotal Mechanisms

  • Farzaneh Afzali
  • Mahdieh SalimiEmail author
Original research article

Abstract

Circular RNAs (circRNAs) possess valuable characteristics for both diagnosis and treatment of several human cancers including breast cancer (BC). In this study, we combined several systems, biology tools and approaches to identify influential BC circRNAs, miRNAs, and related mRNAs as the members of competing endogenous RNAs (ceRNAs) networks and related RNA binding proteins (RBPs) to study and decipher the BC-triggering biological processes and pathways. Rooting from the identified total of 25 co-differentially expressed circRNAs (DECs) between triple negative (TN) and luminal A subtypes of BC from microarray analysis, five hub DECs (hsa_circ_0003227, hsa_circ_0001955, hsa_circ_0020080, hsa_circ_0001666, and hsa_circ_0065173) and top eleven RBPs (AGO1, AGO2, EIF4A3, FMRP, HuR (ELAVL1), IGF2BP1, IGF2BP2, IGF2BP3, EWSR1, FUS, and PTB) were explored to form the upper stream regulatory elements. All the hub circRNAs were regarded as a super sponge having multiple miRNA response elements (MREs). Then, three BC leading miRNAs (hsa-miR-149, hsa-miR-182, and hsa-miR-383) were also introduced from merging several established ceRNAs networks. The predicted 7- and 8-mer MREs matches between hub circRNAs and leading miRNAs ensured their enduring regulatory capability. The mined downstream mRNAs of the circRNAs–miRNAs network then were presented to STRING database to form the PPI network and to decipher the issue from another point of view. The BC interconnected enriched pathways and processes guarantee the merits of the ceRNAs network’s members as targetable therapeutic elements. This study suggested extensive panels of novel therapeutic targets that are in charge of BC progression, hence their impressive role cannot be excluded and needs deeper empirical laboratory designs.

Keywords

circRNA miRNA Breast cancer Regulatory network Microarray analysis 

Notes

Author Contributions

MS conceptualized and supervised the project. FA performed and analyzed all the data. MS and FA have deciphered the analyzed data. FA wrote the manuscript and all the authors read and edited the manuscript.

Funding

This research did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with Ethical Standards

Conflict of Interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplementary material

12539_2019_339_MOESM1_ESM.rar (468 kb)
Supplementary material 1 (TIFF 3684 kb)

References

  1. 1.
    Siegel RL, Miller KD (2017) Jemal A (2017) Cancer statistics. CA Cancer J Clin 67(1):7–30Google Scholar
  2. 2.
    Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP (2011) A ceRNA hypothesis: the Rosetta stone of a hidden RNA language? Cell 146(3):353–358Google Scholar
  3. 3.
    Bosson AD, Zamudio JR, Sharp PA (2014) Endogenous miRNA and target concentrations determine susceptibility to potential ceRNA competition. Mol Cell 56(3):347–359Google Scholar
  4. 4.
    Yang Y, Fan X, Mao M, Song X, Wu P, Zhang Y, Jin Y, Yang Y, Chen L-L, Wang Y (2017) Extensive translation of circular RNAs driven by N 6-methyladenosine. Cell Res 27(5):626Google Scholar
  5. 5.
    Danan M, Schwartz S, Edelheit S, Sorek R (2011) Transcriptome-wide discovery of circular RNAs in Archaea. Nucleic Acids Res 40(7):3131–3142Google Scholar
  6. 6.
    Zhang X-O, Wang H-B, Zhang Y, Lu X, Chen L-L, Yang L (2014) Complementary sequence-mediated exon circularization. Cell 159(1):134–147Google Scholar
  7. 7.
    Zhang Y, Zhang X-O, Chen T, Xiang J-F, Yin Q-F, Xing Y-H, Zhu S, Yang L, Chen L-L (2013) Circular intronic long noncoding RNAs. Mol Cell 51(6):792–806Google Scholar
  8. 8.
    Li Z, Huang C, Bao C, Chen L, Lin M, Wang X, Zhong G, Yu B, Hu W, Dai L (2015) Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol 22(3):256Google Scholar
  9. 9.
    Xu S, Zhou L, Ponnusamy M, Zhang L, Dong Y, Zhang Y, Wang Q, Liu J, Wang K (2018) A comprehensive review of circRNA: from purification and identification to disease marker potential. PeerJ 6:e5503Google Scholar
  10. 10.
    Lü L, Sun J, Shi P, Kong W, Xu K, He B, Zhang S, Wang J (2017) Identification of circular RNAs as a promising new class of diagnostic biomarkers for human breast cancer. Oncotarget 8(27):44096Google Scholar
  11. 11.
    Wu J, Jiang Z, Chen C, Hu Q, Fu Z, Chen J, Wang Z, Wang Q, Li A, Marks JR (2018) CircIRAK3 sponges miR-3607 to facilitate breast cancer metastasis. Cancer Lett 430:179–192Google Scholar
  12. 12.
    Liang H-F, Zhang X-Z, Liu B-G, Jia G-T, Li W-L (2017) Circular RNA circ-ABCB10 promotes breast cancer proliferation and progression through sponging miR-1271. Am J Cancer Res 7(7):1566Google Scholar
  13. 13.
    Nasri-Nasrabadi P, Zareian S, Nayeri Z, Salmanipour R, Parsafar S, Gharib E, Asadzadeh-Aghdaei H, Zali MR (2019) A detailed image of rutin underlying intracellular signaling pathways in human SW480 colorectal cancer cells based on miRNAs-lncRNAs-mRNAs-TFs interactions. J Cell Physiol 234(9):15570–15580Google Scholar
  14. 14.
    Gharib E, Kouhsari SM, Izad M (2018) Punica granatum L Fruit aqueous extract suppresses reactive oxygen species-mediated p53/p65/miR-145 expressions followed by elevated levels of irs-1 in alloxan-diabetic rats. Cell J 19(4):520Google Scholar
  15. 15.
    Cai Y, Yu X, Hu S, Yu J (2009) A brief review on the mechanisms of miRNA regulation. Genom Proteom Bioinform 7(4):147–154Google Scholar
  16. 16.
    O'Day E, Lal A (2010) MicroRNAs and their target gene networks in breast cancer. Breast Cancer Res 12(2):201Google Scholar
  17. 17.
    Imani S, Wei C, Cheng J, Khan MA, Fu S, Yang L, Tania M, Zhang X, Xiao X, Zhang X (2017) MicroRNA-34a targets epithelial to mesenchymal transition-inducing transcription factors (EMT-TFs) and inhibits breast cancer cell migration and invasion. Oncotarget 8(13):21362Google Scholar
  18. 18.
    Li P, Sheng C, Huang L, Zhang H, Huang L, Cheng Z, Zhu Q (2014) MiR-183/-96/-182 cluster is up-regulated in most breast cancers and increases cell proliferation and migration. Breast Cancer Res 16(6):473Google Scholar
  19. 19.
    Abdelmohsen K, Gorospe M (2010) Posttranscriptional regulation of cancer traits by HuR. Wiley Interdiscip Rev RNA 1(2):214–229Google Scholar
  20. 20.
    Hentze MW, Preiss T (2013) Circular RNAs: splicing's enigma variations. EMBO J 32(7):923–925Google Scholar
  21. 21.
    Lécuyer E, Yoshida H, Parthasarathy N, Alm C, Babak T, Cerovina T, Hughes TR, Tomancak P, Krause HM (2007) Global analysis of mRNA localization reveals a prominent role in organizing cellular architecture and function. Cell 131(1):174–187Google Scholar
  22. 22.
    Glisovic T, Bachorik JL, Yong J, Dreyfuss G (2008) RNA-binding proteins and post-transcriptional gene regulation. FEBS Lett 582(14):1977–1986Google Scholar
  23. 23.
    Zheng L, Zhang Z, Zhang S, Guo Q, Zhang F, Gao L, Ni H, Guo X, Xiang C, Xi T (2018) RNA binding protein RNPC1 inhibits breast cancer cell metastasis via activating STARD13-correlated ceRNA network. Mol Pharm 15(6):2123–2132Google Scholar
  24. 24.
    Guo X, Hartley RS (2006) HuR contributes to cyclin E1 deregulation in MCF-7 breast cancer cells. Can Res 66(16):7948–7956Google Scholar
  25. 25.
    Maubant S, Tesson B, Maire V, Ye M, Rigaill G, Gentien D, Cruzalegui F, Tucker GC, Roman-Roman S, Dubois T (2015) Transcriptome analysis of Wnt3a-treated triple-negative breast cancer cells. PLoS ONE 10(4):e0122333Google Scholar
  26. 26.
    Dudekula DB, Panda AC, Grammatikakis I, De S, Abdelmohsen K, Gorospe M (2016) CircInteractome: a web tool for exploring circular RNAs and their interacting proteins and microRNAs. RNA Biol 13(1):34–42Google Scholar
  27. 27.
    Wickham H (2011) ggplot2. Wiley Interdiscip Rev Comput Stat 3(2):180–185Google Scholar
  28. 28.
    Bader GD, Hogue CW (2003) An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinform 4(1):2Google Scholar
  29. 29.
    Silva TC, Colaprico A, Olsen C, D'Angelo F, Bontempi G, Ceccarelli M, Noushmehr H (2016) TCGA Workflow: analyze cancer genomics and epigenomics data using bioconductor packages. F1000Research 5:1542Google Scholar
  30. 30.
    Gao Y, Zhao F (2018) Computational strategies for exploring circular RNAs. Trends Genet 34(5):389–400Google Scholar
  31. 31.
    Li X, Chu C, Pei J, Măndoiu I, Wu Y (2018) CircMarker: a fast and accurate algorithm for circular RNA detection. BMC Genom 19(6):175Google Scholar
  32. 32.
    Rong D, Sun H, Li Z, Liu S, Dong C, Fu K, Tang W, Cao H (2017) An emerging function of circRNA-miRNAs-mRNA axis in human diseases. Oncotarget 8(42):73271Google Scholar
  33. 33.
    D-d Xiong, Y-w Dang, Lin P, D-y Wen, R-q He, D-z Luo, Z-b Feng, Chen G (2018) A circRNA–miRNA–mRNA network identification for exploring underlying pathogenesis and therapy strategy of hepatocellular carcinoma. J Transl Med 16(1):220Google Scholar
  34. 34.
    Nair AA, Niu N, Tang X, Thompson KJ, Wang L, Kocher J-P, Subramanian S, Kalari KR (2016) Circular RNAs and their associations with breast cancer subtypes. Oncotarget 7(49):80967Google Scholar
  35. 35.
    Schiavon G, Smid M, Gupta GP, Redana S, Santini D, Martens JW (2012) Heterogeneity of breast cancer: gene signatures and beyond. In: Russo A, Iacobelli S, Iovanna J (eds) Diagnostic, prognostic and therapeutic value of gene signatures. Humana Press, New York, pp 13–25Google Scholar
  36. 36.
    Giza DE, Vasilescu C, Calin GA (2014) MicroRNAs and ceRNAs: therapeutic implications of RNA networks. Expert Opin Biol Ther 14(9):1285–1293Google Scholar
  37. 37.
    Ivanov A, Memczak S, Wyler E, Torti F, Porath HT, Orejuela MR, Piechotta M, Levanon EY, Landthaler M, Dieterich C (2015) Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. Cell Rep 10(2):170–177Google Scholar
  38. 38.
    Ashwal-Fluss R, Meyer M, Pamudurti NR, Ivanov A, Bartok O, Hanan M, Evantal N, Memczak S, Rajewsky N, Kadener S (2014) circRNA biogenesis competes with pre-mRNA splicing. Mol Cell 56(1):55–66Google Scholar
  39. 39.
    Venables JP, Klinck R, Koh C, Gervais-Bird J, Bramard A, Inkel L, Durand M, Couture S, Froehlich U, Lapointe E (2009) Cancer-associated regulation of alternative splicing. Nat Struct Mol Biol 16(6):670Google Scholar
  40. 40.
    Mayr C, Bartel DP (2009) Widespread shortening of 3′ UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138(4):673–684Google Scholar
  41. 41.
    Grimson A, Farh KK-H, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP (2007) MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27(1):91–105Google Scholar
  42. 42.
    Qi X, Zhang D-H, Wu N, Xiao J-H, Wang X, Ma W (2015) ceRNA in cancer: possible functions and clinical implications. J Med Genet 52(10):710–718Google Scholar
  43. 43.
    He Y, Yu D, Zhu L, Zhong S, Zhao J, Tang J (2018) miR-149 in human cancer: a systemic review. J Cancer 9(2):375Google Scholar
  44. 44.
    Tsai H-P, Huang S-F, Li C-F, Chien H-T, Chen S-C (2018) Differential microRNA expression in breast cancer with different onset age. PLoS ONE 13(1):e0191195Google Scholar
  45. 45.
    Sharifi M, Moridnia A (2017) Apoptosis-inducing and antiproliferative effect by inhibition of miR-182-5p through the regulation of CASP9 expression in human breast cancer. Cancer Gene Ther 24(2):75Google Scholar
  46. 46.
    Gilam A, Conde J, Weissglas-Volkov D, Oliva N, Friedman E, Artzi N, Shomron N (2016) Local microRNA delivery targets Palladin and prevents metastatic breast cancer. Nat Commun 7:12868Google Scholar
  47. 47.
    Selcuklu S, Yakicier M, Erson A (2009) An investigation of microRNAs mapping to breast cancer related genomic gain and loss regions. Cancer Genet Cytogenet 189(1):15–23Google Scholar
  48. 48.
    He Z, Cen D, Luo X, Li D, Li P, Liang L, Meng Z (2013) Downregulation of miR-383 promotes glioma cell invasion by targeting insulin-like growth factor 1 receptor. Med Oncol 30(2):557Google Scholar
  49. 49.
    Harvey RF, Smith TS, Mulroney T, Queiroz RM, Pizzinga M, Dezi V, Villenueva E, Ramakrishna M, Lilley KS, Willis AE (2018) Trans-acting translational regulatory RNA binding proteins. Wiley Interdiscip Rev RNA 9(3):e1465Google Scholar
  50. 50.
    Flint DJ, Tonner E, Allan GJ (2000) Insulin-like growth factor binding proteins: IGF-dependent and-independent effects in the mammary gland. J Mammary Gland Biol Neoplasia 5(1):65–73Google Scholar
  51. 51.
    Patel AV, Cheng I, Canzian F, Le Marchand L, Thun MJ, Berg CD, Buring J, Calle EE, Chanock S, Clavel-Chapelon F (2008) IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3). PLoS ONE 3(7):e2578Google Scholar
  52. 52.
    He X, Arslan A, Ho T, Yuan C, Stampfer M, Beck W (2014) Involvement of polypyrimidine tract-binding protein (PTBP1) in maintaining breast cancer cell growth and malignant properties. Oncogenesis 3(1):e84Google Scholar
  53. 53.
    Wang J, Guo Y, Chu H, Guan Y, Bi J, Wang B (2013) Multiple functions of the RNA-binding protein HuR in cancer progression, treatment responses and prognosis. Int J Mol Sci 14(5):10015–10041Google Scholar
  54. 54.
    Chou S-D, Murshid A, Eguchi T, Gong J, Calderwood SK (2015) HSF1 regulation of β-catenin in mammary cancer cells through control of HuR/elavL1 expression. Oncogene 34(17):2178Google Scholar
  55. 55.
    Liu Y, Li J, Ma Z, Zhang J, Wang Y, Yu Z, Lin X, Xu Z, Su Q, An L (2019) Oncogenic functions of protein kinase D2 and D3 in regulating multiple cancer-related pathways in breast cancer. Cancer Med 8(2):729–741Google Scholar
  56. 56.
    Ke H, Zhao L, Feng X, Xu H, Zou L, Yang Q, Su X, Peng L, Jiao B (2016) NEAT1 is required for survival of breast cancer cells through FUS and miR-548. Gene Regul Syst Biol 10:GRSB.S29414Google Scholar
  57. 57.
    Lucá R, Averna M, Zalfa F, Vecchi M, Bianchi F, La Fata G, Del Nonno F, Nardacci R, Bianchi M, Nuciforo P (2013) The fragile X protein binds mRNAs involved in cancer progression and modulates metastasis formation. EMBO Mol Med 5(10):1523–1536Google Scholar
  58. 58.
    Morettin A, Paris G, Bouzid Y, Baldwin RM, Falls TJ, Bell JC, Côté J (2017) Tudor domain containing protein 3 promotes tumorigenesis and invasive capacity of breast cancer cells. Sci Rep 7(1):5153Google Scholar
  59. 59.
    Ye Z, Jin H, Qian Q (2015) Argonaute 2: a novel rising star in cancer research. J Cancer 6(9):877Google Scholar
  60. 60.
    Bellissimo T, Tito C, Ganci F, Sacconi A, Masciarelli S, Di Martino G, Porta N, Cirenza M, Sorci M, De Angelis L (2019) Argonaute 2 drives miR-145-5p-dependent gene expression program in breast cancer cells. Cell Death Dis 10(1):17Google Scholar
  61. 61.
    Scully OJ, Bay B-H, Yip G, Yu Y (2012) Breast cancer metastasis. Cancer Genom Proteom 9(5):311–320Google Scholar
  62. 62.
    Neupane M, Clark AP, Landini S, Birkbak NJ, Eklund AC, Lim E, Culhane AC, Barry WT, Schumacher SE, Beroukhim R (2016) MECP2 is a frequently amplified oncogene with a novel epigenetic mechanism that mimics the role of activated RAS in malignancy. Cancer Discov 6(1):45–58Google Scholar
  63. 63.
    Ray BK, Dhar S, Henry CJ, Rich A, Ray A (2012) Epigenetic regulation by Z-DNA silencer function controls cancer-associated ADAM-12 expression in breast cancer: cross talk between MECP2 and NFI transcription factor family. Cancer Res 2601:2012Google Scholar
  64. 64.
    Guo S, Liu M, Gonzalez-Perez RR (2011) Role of Notch and its oncogenic signaling crosstalk in breast cancer. Biochim Biophys Acta (BBA) Rev Cancer 1815(2), 197–213.Google Scholar
  65. 65.
    Imatani A, Callahan R (2000) Identification of a novel NOTCH-4/INT-3 RNA species encoding an activated gene product in certain human tumor cell lines. Oncogene 19(2):223Google Scholar
  66. 66.
    Zhang Z, Wang H, Ikeda S, Fahey F, Bielenberg D, Smits P, Hauschka PV (2010) Notch3 in human breast cancer cell lines regulates osteoblast-cancer cell interactions and osteolytic bone metastasis. Am J Pathol 177(3):1459–1469Google Scholar
  67. 67.
    Soares R, Balogh G, Guo S, Gartner F, Russo J, Schmitt F (2004) Evidence for the notch signaling pathway on the role of estrogen in angiogenesis. Mol Endocrinol 18(9):2333–2343Google Scholar
  68. 68.
    Weijzen S, Rizzo P, Braid M, Vaishnav R, Jonkheer SM, Zlobin A, Osborne BA, Gottipati S, Aster JC, Hahn WC (2002) Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med 8(9):979Google Scholar
  69. 69.
    Hong D, Messier TL, Tye CE, Dobson JR, Fritz AJ, Sikora KR, Browne G, Stein JL, Lian JB, Stein GS (2017) Runx1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition. Oncotarget 8(11):17610Google Scholar
  70. 70.
    Browne G, Taipaleenmäki H, Bishop NM, Madasu SC, Shaw LM, Van Wijnen AJ, Stein JL, Stein GS, Lian JB (2015) Runx1 is associated with breast cancer progression in MMTV-PyMT transgenic mice and its depletion in vitro inhibits migration and invasion. J Cell Physiol 230(10):2522–2532Google Scholar
  71. 71.
    Azimi I, Roberts-Thomson S, Monteith G (2014) Calcium influx pathways in breast cancer: opportunities for pharmacological intervention. Br J Pharmacol 171(4):945–960Google Scholar
  72. 72.
    Grice DM, Vetter I, Faddy HM, Kenny PA, Roberts-Thomson SJ, Monteith GR (2010) The Golgi calcium pump secretory pathway calcium ATPase 1 (SPCA1) is a key regulator of insulin-like growth factor receptor (IGF1R) processing in the basal-like breast cancer cell line MDA-MB-231. J Biol Chem M110:163329Google Scholar
  73. 73.
    VanHouten J, Sullivan C, Bazinet C, Ryoo T, Camp R, Rimm DL, Chung G, Wysolmerski J (2010) PMCA2 regulates apoptosis during mammary gland involution and predicts outcome in breast cancer. Proc Natl Acad Sci 107(25):11405–11410Google Scholar
  74. 74.
    Nagano M, Hoshino D, Koshikawa N, Akizawa T, Seiki M (2012) Turnover of focal adhesions and cancer cell migration. Int J Cell Biol 2012:310616Google Scholar
  75. 75.
    Ghiso JAA (2002) Inhibition of FAK signaling activated by urokinase receptor induces dormancy in human carcinoma cells in vivo. Oncogene 21(16):2513Google Scholar
  76. 76.
    Luo M, Fan H, Nagy T, Wei H, Wang C, Liu S, Wicha MS, Guan J-L (2009) Mammary epithelial-specific ablation of the focal adhesion kinase suppresses mammary tumorigenesis by affecting mammary cancer stem/progenitor cells. Can Res 69(2):466–474Google Scholar
  77. 77.
    Frisch SM, Screaton RA (2001) Anoikis mechanisms. Curr Opin Cell Biol 13(5):555–562Google Scholar
  78. 78.
    Luo M, Guan J-L (2010) Focal adhesion kinase: a prominent determinant in breast cancer initiation, progression and metastasis. Cancer Lett 289(2):127–139Google Scholar

Copyright information

© International Association of Scientists in the Interdisciplinary Areas 2019

Authors and Affiliations

  1. 1.Medical Biotechnology DepartmentNational Institute of Genetic Engineering and Biotechnology (NIGEB)TehranIran
  2. 2.Pars Silico Bioinformatics LaboratoryTehranIran

Personalised recommendations