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Mapping genetic variability in mature miRNAs and miRNA binding sites in prostate cancer

Abstract

MicroRNAs (miRNAs) regulate diverse cancer hallmarks through sequence-specific regulation of gene expression, so genetic variability in their seed sequences or target sites could be responsible for cancer initiation or progression. While several efforts have been made to predict the locations of single nucleotide variants (SNVs) at miRNA target sites and associate them with cancer risk and susceptibility, there have been few direct assessments of SNVs in both mature miRNAs and their target sites to assess their impact on miRNA function in cancers. Using genome-wide target capture of miRNAs and miRNA-binding sites followed by deep sequencing in prostate cancer cell lines, here we identified prostate cancer-specific SNVs in mature miRNAs and their target binding sites. SNV rs9860655 in the mature sequence of miR-570 was not present in benign prostate hyperplasia (BPH) tissue or cell lines but was detectable in clinical prostate cancer tissue samples and adjacent normal tissue. SLC45A3 (prostein), a putative oncogene target of miR-1178, was highly upregulated in PC3 cells harboring an miR-1178 seed sequence SNV. Finally, systematic assessment of losses and gains of miRNA targets through 3′UTR SNVs revealed SNV-associated changes in target oncogene and tumor suppressor gene expression that might be associated with prostate carcinogenesis. Further work is required to systematically assess the functional effects of miRNA SNVs.

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References

  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.

    PubMed  Article  Google Scholar 

  2. 2.

    Ablin RJ. The need for personalized therapy and companion diagnostics in prostate cancer. Biomark Med. 2011;5:281–3.

    PubMed  Article  Google Scholar 

  3. 3.

    Sedelaar JP, Schalken JA. The need for a personalized approach for prostate cancer management. BMC Med. 2015;13:109.

    PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    McGrath S, Christidis D, Perera M, Hong SK, Manning T, Vela I, et al. Prostate cancer biomarkers: Are we hitting the mark? Prostate Int. 2016;4:130–5.

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Ottman R, Nguyen C, Lorch R, Chakrabarti R. MicroRNA expressions associated with progression of prostate cancer cells to antiandrogen therapy resistance. Mol Cancer. 2014;13:1.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6.

    Di Leva G, Garofalo M, Croce CM. MicroRNAs in cancer. Annu Rev Pathol. 2014;9:287–314.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Wuchty S, Arjona D, Bozdag S, Bauer PO. Involvement of microRNA families in cancer. Nucleic Acids Res. 2012;40:8219–26.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Fletcher CE, Godfrey JD, Shibakawa A, Bushell M, Bevan CL. A novel role for GSK3beta as a modulator of Drosha microprocessor activity and MicroRNA biogenesis. Nucleic Acids Res. 2017;45:2809–28.

    CAS  PubMed  Google Scholar 

  9. 9.

    Feng Y, Zhang X, Graves P, Zeng Y. A comprehensive analysis of precursor microRNA cleavage by human Dicer. RNA. 2012;18:2083–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Lehrbach NJ, Miska EA. Regulation of pre-miRNA Processing. Adv Exp Med Biol. 2011;700:67–75.

    PubMed  Article  Google Scholar 

  11. 11.

    Salomon WE, Jolly SM, Moore MJ, Zamore PD, Serebrov V. Single-molecule imaging reveals that argonaute reshapes the binding properties of its nucleic acid guides. Cell. 2015;162:84–95.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Davis-Dusenbery BN, Hata A. Mechanisms of control of microRNA biogenesis. J Biochem. 2010;148:381–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Kertesz M, Iovino N, Unnerstall U, Gaul U, Segal E. The role of site accessibility in microRNA target recognition. Nat Genet. 2007;39:1278–84.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Gong J, Tong Y, Zhang HM, Wang K, Hu T, Shan G, et al. Genome-wide identification of SNPs in microRNA genes and the SNP effects on microRNA target binding and biogenesis. Hum Mutat. 2012;33:254–63.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y, et al. Punctuated evolution of prostate cancer genomes. Cell. 2013;153:666–77.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Kar SP, Beesley J, Amin Al Olama A, Michailidou K, Tyrer J, Kote-Jarai Z, et al. Genome-wide meta-analyses of breast, ovarian, and prostate cancer association studies identify multiple new susceptibility loci shared by at least two cancer types. Cancer Discov. 2016;6:1052–67.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Liu H, Wang B, Han C. Meta-analysis of genome-wide and replication association studies on prostate cancer. Prostate. 2011;71:209–24.

    PubMed  Article  Google Scholar 

  19. 19.

    Stegeman S, Amankwah E, Klein K, O’Mara TA, Kim D, Lin HY, et al. A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer. Cancer Discov. 2015;5:368–79.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Pekin D, Skhiri Y, Baret JC, Le Corre D, Mazutis L, Salem CB, et al. Quantitative and sensitive detection of rare mutations using droplet-based microfluidics. Lab Chip. 2011;11:2156–66.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Heredia NJ, Belgrader P, Wang S, Koehler R, Regan J, Cosman AM, et al. Droplet Digital PCR quantitation of HER2 expression in FFPE breast cancer samples. Methods. 2013;59:S20–23.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Cooper CS, Eeles R, Wedge DC, Van Loo P, Gundem G, Alexandrov LB, et al. Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. Nat Genet. 2015;47:367–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007;27:91–105.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Chen Y, Wang X. miRDB: an online database for prediction of functional microRNA targets. Nucleic Acids Res. 2020;48:D127–D131.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Hu Z, Chen J, Tian T, Zhou X, Gu H, Xu L, et al. Genetic variants of miRNA sequences and non-small cell lung cancer survival. J Clin Invest. 2008;118:2600–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120:15–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Xu J, Kalos M, Stolk JA, Zasloff EJ, Zhang X, Houghton RL, et al. Identification and characterization of prostein, a novel prostate-specific protein. Cancer Res. 2001;61:1563–8.

    CAS  PubMed  Google Scholar 

  28. 28.

    Musiyenko A, Bitko V, Barik S. Ectopic expression of miR-126*, an intronic product of the vascular endothelial EGF-like 7 gene, regulates prostein translation and invasiveness of prostate cancer LNCaP cells. J Mol Med (Berl). 2008;86:313–22.

    CAS  Article  Google Scholar 

  29. 29.

    Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    CAS  Article  Google Scholar 

  30. 30.

    Tan H, Zeng C, Xie J, Alghamdi NJ, Song Y, Zhang H, et al. Effects of interferons and double-stranded RNA on human prostate cancer cell apoptosis. Oncotarget. 2015;6:39184–95.

    PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Wang B, Hasan MK, Alvarado E, Yuan H, Wu H, Chen WY. NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response. Oncogene. 2011;30:907–21.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Frank SB, Berger PL, Ljungman M, Miranti CK. Human prostate luminal cell differentiation requires NOTCH3 induction by p38-MAPK and MYC. J Cell Sci. 2017;130:1952–64.

    CAS  PubMed  Google Scholar 

  33. 33.

    Kim AR, Gu MJ. The clinicopathologic significance of Notch3 expression in prostate cancer. Int J Clin Exp Pathol. 2019;12:3535–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Pedrosa AR, Graca JL, Carvalho S, Peleteiro MC, Duarte A, Trindade A. Notch signaling dynamics in the adult healthy prostate and in prostatic tumor development. Prostate. 2016;76:80–96.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Paltoglou S, Das R, Townley SL, Hickey TE, Tarulli GA, Coutinho I, et al. Novel androgen receptor coregulator GRHL2 exerts both oncogenic and antimetastatic functions in prostate cancer. Cancer Res. 2017;77:3417–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Patel MI, Kurek C, Dong Q. The arachidonic acid pathway and its role in prostate cancer development and progression. J Urol. 2008;179:1668–75.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Vainio P, Gupta S, Ketola K, Mirtti T, Mpindi JP, Kohonen P, et al. Arachidonic acid pathway members PLA2G7, HPGD, EPHX2, and CYP4F8 identified as putative novel therapeutic targets in prostate cancer. Am J Pathol. 2011;178:525–36.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    MacDonald BT, He X. Frizzled and LRP5/6 receptors for Wnt/beta-catenin signaling. Cold Spring Harb Perspect Biol. 2012;4:a007880.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Gupta S, Iljin K, Sara H, Mpindi JP, Mirtti T, Vainio P, et al. FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res. 2010;70:6735–45.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Salameh A, Lee AK, Cardo-Vila M, Nunes DN, Efstathiou E, Staquicini FI, et al. PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3. Proc Natl Acad Sci USA. 2015;112:8403–8.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Jazdzewski K, Murray EL, Franssila K, Jarzab B, Schoenberg DR, de la Chapelle A. Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci USA. 2008;105:7269–74.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Smits KM, Paranjape T, Nallur S, Wouters KA, Weijenberg MP, Schouten LJ, et al. A let-7 microRNA SNP in the KRAS 3′UTR is prognostic in early-stage colorectal cancer. Clin Cancer Res. 2011;17:7723–31.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Saetrom P, Biesinger J, Li SM, Smith D, Thomas LF, Majzoub K, et al. A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis. Cancer Res. 2009;69:7459–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Preskill C, Weidhaas JB. SNPs in microRNA binding sites as prognostic and predictive cancer biomarkers. Crit Rev Oncog. 2013;18:327–40.

    PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Ning Z, Cox AJ, Mullikin JC. SSAHA: a fast search method for large DNA databases. Genome Res. 2001;11:1725–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Kozomara A, Griffiths-Jones S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 2011;39:D152.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Pruitt KD, Katz KS, Sicotte H, Maglott DR. Introducing RefSeq and LocusLink: curated human genome resources at the NCBI. Trends Genet. 2000;16:44–7.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Kent WJ. The human genome browser at UCSC. Genome Res. 2002;12:996–1006.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Rosenbloom KR, Armstrong J, Barber GP, Casper J, Clawson H, Diekhans M, et al. The UCSC Genome Browser database: 2015 update. Nucleic Acids Res. 2015;43:D670–1.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Yates A, Akanni W, Amode MR, Barrell D, Billis K, Carvalho-Silva D, et al. Ensembl 2016. Nucleic Acids Res. 2016;44:D710–6.

    CAS  Article  Google Scholar 

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Funding

This work was supported by National Institutes of Health grant NCI 5P30CA030199, Florida Department of Health, Bankhead-Coley Cancer Research Program 5BC08 and International Prostate Cancer Foundation (IPCF) to RJP.

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Correspondence to Ranjan J. Perera.

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Lee, B., Li, JL., Marchica, J. et al. Mapping genetic variability in mature miRNAs and miRNA binding sites in prostate cancer. J Hum Genet (2021). https://doi.org/10.1038/s10038-021-00934-w

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