DISCOVERIES (ISSN 2359-7232), 2014, April-June

CITATION: 
Ziga Strmsek, Tanja Kunej. Data integration of 104 studies related with microRNA epigenetics revealed that miR-34 gene family is silenced by DNA methylation in the highest number of cancer types. Discoveries 2014, Apr-Jun; 2(2): e18. DOI: 10.15190/d.2014.10

Submitted: June 9, 2014; Revised: June 29, 2014; Accepted: June 29, 2014; Published: June 30, 2014;

GO BACK to 2014, April-June issue 
GO BACK to DISCOVERIES

Data integration of 104 studies related with microRNA epigenetics revealed that miR-34 gene family is silenced by DNA methylation in the highest number of cancer types

Ziga Strmsek (1), Tanja Kunej (1,*)

(1) Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Groblje 3, 1230, Domzale, Slovenia;

*Correspondence to: Tanja Kunej, PhD, Chair of Genetics, Animal Biotechnology and Immunology, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Groblje 3, Slovenia; Phone: 003891-320-3890; Fax: 003861-724-1005; Email: tanja.kunej@bf.uni-lj.si

Abstract

There is an increasing research interest regarding deregulation of microRNA (miRNA) expression by DNA methylation in cancer. The aim of this study was to integrate data from publications and identify miRNA genes shown to be silenced in the highest number of cancer types and thus facilitate biomarker and therapeutic development. We integrated relevant data from 104 published scientific articles. The following databases and bioinformatics tools were used for the analysis: miRBase, miRNA Genomic Viewer, MultAlin, miRNA SNiPer, TargetScan, Ensembl, MethPrimer, TarBase, miRecords, and ChIPBase. Among 2578 currently known human miRNAs and 158 known to be regulated by DNA methylation, miR-34 gene family (miR-34a, -34b, and -34c) was shown to be silenced by DNA methylation in the highest number of cancer types. Consequently, we developed the miR-34 gene family regulatory atlas, consisting of its upstream regulators and downstream targets including transcription factor binding sites (TFBSs), CpG islands, genetic variability and overlapping QTL. MicroRNA-34 gene family has a potential as a cancer biomarker and target for epigenetic drugs. This potential has already been recognized as MRX34 is well into phase I studies. The developed miR-34 gene family regulatory atlas presented in this study provides a starting point for further analyses and could thus facilitate development of therapeutics.

Access full text of the manuscript here: See full text (pdf)

References

1.   Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009 Jan; 19(1): 92-105.

2.   Kunej T, Godnic I, Horvat S, Zorc M, Calin GA. Cross talk between microRNA and coding cancer genes. Cancer J. 2012 2012 May-Jun; 18(3): 223-231.

3.   Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004 Mar; 101(9): 2999-3004.

4.   Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM. bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 2003 Apr; 113(1): 25-36.

5.   Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993 Dec; 75(5): 843-854.

6.   Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer 2006 Nov; 6(11): 857-866.

7.   Gaur A, Jewell DA, Liang Y, Ridzon D, Moore JH, Chen C, et al. Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Res. 2007 Mar; 67(6): 2456-2468.

8.   Lu C, Tej SS, Luo S, Haudenschild CD, Meyers BC, Green PJ. Elucidation of the small RNA component of the transcriptome. Science 2005 Sep; 309(5740): 1567-1569.

9.   Fabbri M, Ivan M, Cimmino A, Negrini M, Calin GA. Regulatory mechanisms of microRNAs involvement in cancer. Expert Opin Biol Ther. 2007 Jul; 7(7): 1009-1019.

10. Agostini M, Knight RA. miR-34: from bench to bedside. Oncotarget 2014 Mar; 5(4): 872–881.

11. Ferdin J, Kunej T, Calin GA. Non-coding RNAs: identification of cancer-associated microRNAs by gene profiling. Technol Cancer Res Treat. 2010 Apr; 9(2): 123-138.

12. Kunej T, Godnic I, Ferdin J, Horvat S, Dovc P, Calin GA. Epigenetic regulation of microRNAs in cancer: an integrated review of literature. Mutat Res. 2011 Dec; 717(1-2): 77-84.

13. Weber B, Stresemann C, Brueckner B, Lyko F. Methylation of human microRNA genes in normal and neoplastic cells. Cell Cycle 2007 May; 6(9): 1001-1005.

14. Saito Y, Liang G, Egger G, Friedman JM, Chuang JC, Coetzee GA, et al. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 2006 Jun; 9(6): 435-443.

15. Kozomara A, Griffiths-Jones S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 2011 Jan; 39(Database issue): D152-157.

16. Li LC, Dahiya R. MethPrimer: designing primers for methylation PCRs. Bioinformatics 2002 Nov; 18(11): 1427-1431.

17. Zorc M, Skok DJ, Godnic I, Calin GA, Horvat S, Jiang Z, et al. Catalog of microRNA seed polymorphisms in vertebrates. PLoS One 2012; 7(1): e30737.

18. Jevsinek Skok D, Godnic I, Zorc M, Horvat S, Dovc P, Kovac M, et al. Genome-wide in silico screening for microRNA genetic variability in livestock species. Anim Genet 2013 Jul.

19. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005 Jan; 120(1): 15-20.

20. Yang JH, Li JH, Jiang S, Zhou H, Qu LH. ChIPBase: a database for decoding the transcriptional regulation of long non-coding RNA and microRNA genes from ChIP-Seq data. Nucleic Acids Res 2013 Jan; 41(Database issue): D177-187.

21. Sethupathy P, Corda B, Hatzigeorgiou AG. TarBase: A comprehensive database of experimentally supported animal microRNA targets. RNA 2006 Feb; 12(2): 192-197.

22. Xiao F, Zuo Z, Cai G, Kang S, Gao X, Li T. miRecords: an integrated resource for microRNA-target interactions. Nucleic Acids Res. 2009 Jan; 37(Database issue): D105-110.

23. Corpet F. Multiple sequence alignment with hierarchical clustering. Nucleic Acids Res. 1988 Nov; 16(22): 10881-10890.

24. Lodygin D, Tarasov V, Epanchintsev A, Berking C, Knyazeva T, Körner H, et al. Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle 2008 Aug; 7(16): 2591-2600.

25. Kozaki K, Imoto I, Mogi S, Omura K, Inazawa J. Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in oral cancer. Cancer Res 2008 Apr; 68(7): 2094-2105.

26. Zhang L, Volinia S, Bonome T, Calin GA, Greshock J, Yang N, et al. Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer. Proc Natl Acad Sci U S A 2008 May; 105(19): 7004-7009.

27. Toyota M, Suzuki H, Sasaki Y, Maruyama R, Imai K, Shinomura Y, et al. Epigenetic silencing of microRNA-34b/c and B-cell translocation gene 4 is associated with CpG island methylation in colorectal cancer. Cancer Res 2008 Jun; 68(11): 4123-4132.

28. Lujambio A, Calin GA, Villanueva A, Ropero S, Sánchez-Céspedes M, Blanco D, et al. A microRNA DNA methylation signature for human cancer metastasis. Proceedings of the National Academy of Sciences 2008; 105(36): 13556-13561.

29. Roman-Gomez J, Agirre X, Jiménez-Velasco A, Arqueros V, Vilas-Zornoza A, Rodriguez-Otero P, et al. Epigenetic Regulation of MicroRNAs in Acute Lymphoblastic Leukemia. Journal of Clinical Oncology 2009; 27(8): 1316-1322.

30. Pigazzi M, Manara E, Baron E, Basso G. miR-34b targets cyclic AMP-responsive element binding protein in acute myeloid leukemia. Cancer Res. 2009 Mar; 69(6): 2471-2478.

31. Corney DC, Hwang CI, Matoso A, Vogt M, Flesken-Nikitin A, Godwin AK, et al. Frequent downregulation of miR-34 family in human ovarian cancers. Clin Cancer Res. 2010 Feb; 16(4): 1119-1128.

32. Suzuki H, Yamamoto E, Nojima M, Kai M, Yamano HO, Yoshikawa K, et al. Methylation-associated silencing of microRNA-34b/c in gastric cancer and its involvement in an epigenetic field defect. Carcinogenesis 2010 Dec; 31(12): 2066-2073.

33. Dudziec E, Miah S, Choudhry HM, Owen HC, Blizard S, Glover M, et al. Hypermethylation of CpG islands and shores around specific microRNAs and mirtrons is associated with the phenotype and presence of bladder cancer. Clin Cancer Res. 2011 Mar; 17(6): 1287-1296.

34. Vogt M, Munding J, Grüner M, Liffers ST, Verdoodt B, Hauk J, et al. Frequent concomitant inactivation of miR-34a and miR-34b/c by CpG methylation in colorectal, pancreatic, mammary, ovarian, urothelial, and renal cell carcinomas and soft tissue sarcomas. Virchows Arch. 2011 Mar; 458(3): 313-322.

35. Chim CS, Wong KY, Qi Y, Loong F, Lam WL, Wong LG, et al. Epigenetic inactivation of the miR-34a in hematological malignancies. Carcinogenesis 2010; 31(4): 745-750.

36. Chim CS, Wong KY, Leung CY, Chung LP, Hui PK, Chan SY, et al. Epigenetic inactivation of the hsa-miR-203 in haematological malignancies. J Cell Mol Med. 2011 Dec; 15(12): 2760-2767.

37. Wang Z, Chen Z, Gao Y, Li N, Li B, Tan F, et al. DNA hypermethylation of microRNA-34b/c has prognostic value for stage I non-small cell lung cancer. Cancer Biol Ther. 2011 Mar; 11(5): 490-496.

38. Botezatu A, Goia-Rusanu CD, Iancu IV, Huica I, Plesa A, Socolov D, et al. Quantitative analysis of the relationship between microRNA-124a, -34b and -203 gene methylation and cervical oncogenesis. Mol Med Report 2011 2011 Jan-Feb; 4(1): 121-128.

39. Chen X, Hu H, Guan X, Xiong G, Wang Y, Wang K, et al. CpG island methylation status of miRNAs in esophageal squamous cell carcinoma. Int J Cancer 2012 Apr; 130(7): 1607-1613.

40. Kalimutho M, Di Cecilia S, Del Vecchio Blanco G, Roviello F, Sileri P, Cretella M, et al. Epigenetically silenced miR-34b/c as a novel faecal-based screening marker for colorectal cancer. Br J Cancer 2011 May; 104(11): 1770-1778.

41. Kubo T, Toyooka S, Tsukuda K, Sakaguchi M, Fukazawa T, Soh J, et al. Epigenetic silencing of microRNA-34b/c plays an important role in the pathogenesis of malignant pleural mesothelioma. Clin Cancer Res. 2011 Aug; 17(15): 4965-4974.

42. Watanabe K, Emoto N, Hamano E, Sunohara M, Kawakami M, Kage H, et al. Genome structure-based screening identified epigenetically silenced microRNA associated with invasiveness in non-small-cell lung cancer. Int J Cancer 2012 Jun; 130(11): 2580-2590.

43. Mazar J, Khaitan D, DeBlasio D, Zhong C, Govindarajan SS, Kopanathi S, et al. Epigenetic regulation of microRNA genes and the role of miR-34b in cell invasion and motility in human melanoma. PLoS One 2011; 6(9): e24922.

44. Wong KY, Yim RL, So CC, Jin DY, Liang R, Chim CS. Epigenetic inactivation of the MIR34B/C in multiple myeloma. Blood 2011 Nov; 118(22): 5901-5904.

45. Tanaka N, Toyooka S, Soh J, Kubo T, Yamamoto H, Maki Y, et al. Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer. Lung Cancer 2012 Apr; 76(1): 32-38.

46. Hiroki E, Suzuki F, Akahira J, Nagase S, Ito K, Sugawara J, et al. MicroRNA-34b functions as a potential tumor suppressor in endometrial serous adenocarcinoma. Int J Cancer 2012 Aug; 131(4): E395-404.

47. Yu F, Jiao Y, Zhu Y, Wang Y, Zhu J, Cui X, et al. MicroRNA 34c gene down-regulation via DNA methylation promotes self-renewal and epithelial-mesenchymal transition in breast tumor-initiating cells. J Biol Chem 2012 Jan; 287(1): 465-473.

48. Tsai K-W, Kao H-W, Chen H-C, Chen S-J, Lin W-c. Epigenetic control of the expression of a primate-specific microRNA cluster in human cancer cells. Epigenetics 2009; 4(8): 587-592.

49. Tsai KW, Wu CW, Hu LY, Li SC, Liao YL, Lai CH, et al. Epigenetic regulation of miR-34b and miR-129 expression in gastric cancer. Int J Cancer 2011 Dec; 129(11): 2600-2610.

50. Dong F, Lou D. MicroRNA-34b/c suppresses uveal melanoma cell proliferation and migration through multiple targets. Mol Vis. 2012; 18: 537-546.

51. Roy S, Levi E, Majumdar AP, Sarkar FH. Expression of miR-34 is lost in colon cancer which can be re-expressed by a novel agent CDF. J Hematol Oncol. 2012; 5: 58.

52. Xie K, Liu J, Chen J, Dong J, Ma H, Liu Y, et al. Methylation-associated silencing of microRNA-34b in hepatocellular carcinoma cancer. Gene 2014 Jun; 543(1): 101-107.

53. He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, et al. A microRNA component of the p53 tumour suppressor network. Nature 2007 Jun; 447(7148): 1130-1134.

54. Chim CS, Wan TS, Wong KY, Fung TK, Drexler HG, Wong KF. Methylation of miR-34a, miR-34b/c, miR-124-1 and miR-203 in Ph-negative myeloproliferative neoplasms. J Transl Med. 2011; 9: 197.

55. Agostini M, Knight RA. miR-34: from bench to bedside. Oncotarget 2014 Mar.

56. Welch C, Chen Y, Stallings RL. MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells. Oncogene 2007 Jul; 26(34): 5017-5022.

57. Baer C, Claus R, Plass C. Genome-Wide Epigenetic Regulation of miRNAs in Cancer. Cancer Res. 2013 Jan; 73(2): 473-477.

58. Soucek L, Whitfield J, Martins CP, Finch AJ, Murphy DJ, Sodir NM, et al. Modelling Myc inhibition as a cancer therapy. Nature 2008 Oct; 455(7213): 679-683.

59. Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 2011 Feb; 17(2): 211-215.

60. Hagman Z, Larne O, Edsjö A, Bjartell A, Ehrnström RA, Ulmert D, et al. miR-34c is downregulated in prostate cancer and exerts tumor suppressive functions. Int J Cancer 2010 Dec; 127(12): 2768-2776.

61. Wiggins JF, Ruffino L, Kelnar K, Omotola M, Patrawala L, Brown D, et al. Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res. 2010 Jul; 70(14): 5923-5930.

62. Ling H, Fabbri M, Calin GA. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov. 2013 Nov; 12(11): 847-865.

63. Hogan NM, Joyce MR, Kerin MJ. MicroRNA expression in colorectal cancer. Cancer Biomark. 2012; 11(6): 239-243.

GO BACK to the 2014, April-June issue 
GO BACK to DISCOVERIES 
MEET OUR EDITORIAL BOARD 
SUBMIT A MANUSCRIPT

 Email us at info@discoveriesjournals.org if you have any questions.