MicroRNAs: Promising Potential Targets for Cancer Treatment

authors:

avatar Mohammad Hashemi ORCID 1 , 2 , *

Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
Gene, Cell and Tissue: Vol.3, issue 4; e42864
published online: October 17, 2016
article type: Editorial
received: October 7, 2016
accepted: October 9, 2016
DOI: https://doi.org/10.17795/gct-42864

how to cite: Hashemi M. MicroRNAs: Promising Potential Targets for Cancer Treatment. Gene Cell Tissue. 2016;3(4):e42864. https://doi.org/10.17795/gct-42864.

MicroRNAs (miRNAs) are single-stranded, non-coding RNAs, approximately 19 to 22 nucleotides in length that function as negative regulators of gene expression. MicroRNAs genes are transcribed by RNA polymerase II. The primary miRNA transcript (pri-miRNAs) is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to create mature miRNA (1, 2). In the recent years, there has been heightened interest among investigators to study the role of mircoRNA (miRNA) in cancer development as well as response to treatment in cancer patients since they function as tumor suppressors or oncogenes (3, 4).

Mature miRNAs target the 3’ untranslated region (3’UTR) of mRNA, leading to mRNA degradation or suppression of translation (1, 5). It has been reported that a single miRNA could bind to mRNAs of about 200 genes, therefore miRNAs play an important role in gene regulation (6, 7) and are involved in physiologic and pathologic processes (1), including tumorigenesis (8), proliferation (9) and apoptosis (10).

Single nucleotide polymorphisms (SNPs) located in miRNAs target sites and in miRNAs themselves could affect gene expression and subsequently alter individual susceptibility to cancer and may also be potential disease markers (11-14).

Growing evidence has shown that polymorphism in the miRNAs biogenesis pathway, mature miRNAs and their targets are associated with the risk of various cancers (15-30).

The aberrant miRNAs expression could serve as potential diagnostic and prognostic biomarkers to evaluate tumor initiation, progression and response to treatment in cancer patients. Down-regulation of microRNA-205 has been shown to be correlated with worse distant metastasis-free survival and overall survival of inflammatory breast cancer (31). It has been suggested that miR-26b could serve as a biomarker for inflammation-associated processes in the gastrointestinal system. As miR-26b expression is down-regulated in sporadic colon cancer, it could be used to differentiate between ulcerative colitis associated colorectal carcinoma (UCC) and the sporadic cancer type (32).

It has been reported that down-regulation of miR-26a/miR-148a and miR-148a in tumor tissues contributed to shorter overall survival of gastric cancer patients (33). A meta-analysis performed by Chen et al. (34) proposed that overexpression of miR-21 predicts both poor disease-free survival (DFS) and overall survival (OS) in patients with colorectal cancer. The results of another meta-analysis (35) showed that high expression of miRNA-21 is associated with worse OS in gliomas.

The results of meta-analysis done by Liang et al. (36) indicated that upregulation of miR-203 was not associated with OS. However, high expression of miR-203 was significantly associated with poor OS of cancer patients among Caucasians individuals. On the other hand, in Asians, a better OS association with miR-203 overexpression was determined. According to the findings, ethnicity appears to play an important role in association of miR-203 expression and cancer patient prognosis. The results of meta-analysis showed that down-regulation of miR-218 expression is significantly associated with poorer OS and DFS, and may be a new prognostic biomarker in some cancer types (37).

It has been proposed that circulating levels of miRNA-155 could serve as powerful diagnostic biomarkers for differential diagnosis of liposarcoma (38). Circulating microRNAs have been shown to be potential noninvasive biomarkers for diagnosis of osteosarcoma in Asian populations (39).

The findings of a meta-analysis suggested that decreased microRNAs expression might be promising markers for predicting the survival rate of cervical cancer (40). Overexpression of miR-200c might predict improved survival in females with ovarian cancer and overexpression of the miR-200 family significantly improves overall survival for Asian females (41). It has been shown that upregulation of miR-10b in patients with breast cancer was significantly associated with poor DFS (42).

In summary, dysregulation of miRNAs could serve as a potential novel therapeutic target for cancer treatment.

References

  • 1.

    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281-97. [PubMed ID: 14744438].

  • 2.

    Esquela-Kerscher A, Slack FJ. Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 2006;6(4):259-69. [PubMed ID: 16557279]. https://doi.org/10.1038/nrc1840.

  • 3.

    Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002;99(24):15524-9. [PubMed ID: 12434020]. https://doi.org/10.1073/pnas.242606799.

  • 4.

    Zhang B, Pan X, Cobb GP, Anderson TA. microRNAs as oncogenes and tumor suppressors. Dev Biol. 2007;302(1):1-12. [PubMed ID: 16989803]. https://doi.org/10.1016/j.ydbio.2006.08.028.

  • 5.

    Ambros V. The functions of animal microRNAs. Nature. 2004;431(7006):350-5. [PubMed ID: 15372042]. https://doi.org/10.1038/nature02871.

  • 6.

    He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5(7):522-31. [PubMed ID: 15211354]. https://doi.org/10.1038/nrg1379.

  • 7.

    Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, et al. Combinatorial microRNA target predictions. Nat Genet. 2005;37(5):495-500. [PubMed ID: 15806104]. https://doi.org/10.1038/ng1536.

  • 8.

    Mocellin S, Pasquali S, Pilati P. Oncomirs: from tumor biology to molecularly targeted anticancer strategies. Mini Rev Med Chem. 2009;9(1):70-80. [PubMed ID: 19149661].

  • 9.

    Johnnidis JB, Harris MH, Wheeler RT, Stehling-Sun S, Lam MH, Kirak O, et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature. 2008;451(7182):1125-9. [PubMed ID: 18278031]. https://doi.org/10.1038/nature06607.

  • 10.

    Gong J, Zhang JP, Li B, Zeng C, You K, Chen MX, et al. MicroRNA-125b promotes apoptosis by regulating the expression of Mcl-1, Bcl-w and IL-6R. Oncogene. 2013;32(25):3071-9. [PubMed ID: 22824797]. https://doi.org/10.1038/onc.2012.318.

  • 11.

    Furer V, Greenberg JD, Attur M, Abramson SB, Pillinger MH. The role of microRNA in rheumatoid arthritis and other autoimmune diseases. Clin Immunol. 2010;136(1):1-15. [PubMed ID: 20223711]. https://doi.org/10.1016/j.clim.2010.02.005.

  • 12.

    Saunders MA, Liang H, Li WH. Human polymorphism at microRNAs and microRNA target sites. Proc Natl Acad Sci U S A. 2007;104(9):3300-5. [PubMed ID: 17360642]. https://doi.org/10.1073/pnas.0611347104.

  • 13.

    Bertino JR, Banerjee D, Mishra PJ. Pharmacogenomics of microRNA: a miRSNP towards individualized therapy. Pharmacogenomics. 2007;8(12):1625-7. [PubMed ID: 18085993]. https://doi.org/10.2217/14622416.8.12.1625.

  • 14.

    Mishra PJ, Mishra PJ, Banerjee D, Bertino JR. MiRSNPs or MiR-polymorphisms, new players in microRNA mediated regulation of the cell: Introducing microRNA pharmacogenomics. Cell Cycle. 2008;7(7):853-8. [PubMed ID: 18414050]. https://doi.org/10.4161/cc.7.7.5666.

  • 15.

    Hashemi M, Sanaei S, Mashhadi MA, Hashemi SM, Taheri M, Ghavami S. Association study of hsa-mir-603 rs11014002 polymorphism and risk of breast cancer in a sample of Iranian population. Cell Mol Biol (Noisy-le-grand). 2015;61(8):69-73. [PubMed ID: 26718432].

  • 16.

    Sanaei S, Hashemi M, Rezaei M, Hashemi SM, Bahari G, Ghavami S. Evaluation of the pri-miR-34b/c rs4938723 polymorphism and its association with breast cancer risk. Biomed Rep. 2016;5(1):125-9. [PubMed ID: 27347415]. https://doi.org/10.3892/br.2016.690.

  • 17.

    Hashemi M, Sanaei S, Rezaei M, Bahari G, Hashemi SM, Mashhadi MA, et al. miR-608 rs4919510 C>G polymorphism decreased the risk of breast cancer in an Iranian subpopulation. Exp Oncol. 2016;38(1):57-9. [PubMed ID: 27031722].

  • 18.

    Omrani M, Hashemi M, Eskandari-Nasab E, Hasani SS, Mashhadi MA, Arbabi F, et al. hsa-mir-499 rs3746444 gene polymorphism is associated with susceptibility to breast cancer in an Iranian population. Biomark Med. 2014;8(2):259-67. [PubMed ID: 24521023]. https://doi.org/10.2217/bmm.13.118.

  • 19.

    Zhu W, Zhao J, He J, Qi D, Wang L, Ma X, et al. Genetic variants in the MicroRNA biosynthetic pathway Gemin3 and Gemin4 are associated with a risk of cancer: a meta-analysis. PeerJ. 2016;4:1724. [PubMed ID: 27019773]. https://doi.org/10.7717/peerj.1724.

  • 20.

    Hashemi M, Moradi N, Ziaee SA, Narouie B, Soltani MH, Rezaei M, et al. Association between single nucleotide polymorphism in miR-499, miR-196a2, miR-146a and miR-149 and prostate cancer risk in a sample of Iranian population. J Adv Res. 2016;7(3):491-8. [PubMed ID: 27222754]. https://doi.org/10.1016/j.jare.2016.03.008.

  • 21.

    Hashemi M, Sheybani-Nasab M, Naderi M, Roodbari F, Taheri M. Association of functional polymorphism at the miR-502-binding site in the 3' untranslated region of the SETD8 gene with risk of childhood acute lymphoblastic leukemia, a preliminary report. Tumour Biol. 2014;35(10):10375-9. [PubMed ID: 25048968]. https://doi.org/10.1007/s13277-014-2359-1.

  • 22.

    Hasani SS, Hashemi M, Eskandari-Nasab E, Naderi M, Omrani M, Sheybani-Nasab M. A functional polymorphism in the miR-146a gene is associated with the risk of childhood acute lymphoblastic leukemia: a preliminary report. Tumour Biol. 2014;35(1):219-25. [PubMed ID: 23888320]. https://doi.org/10.1007/s13277-013-1027-1.

  • 23.

    Yin Z, Cui Z, Ren Y, Xia L, Wang Q, Zhang Y, et al. Association between polymorphisms in pre-miRNA genes and risk of lung cancer in a Chinese non-smoking female population. Lung Cancer. 2016;94:15-21. [PubMed ID: 26973201]. https://doi.org/10.1016/j.lungcan.2016.01.013.

  • 24.

    Xu L, Tang W. Associations of Polymorphisms in mir-196a2, mir-146a and mir-149 with Colorectal Cancer Risk: A Meta-Analysis. Pathol Oncol Res. 2016;22(2):261-7. [PubMed ID: 26208586]. https://doi.org/10.1007/s12253-014-9843-1.

  • 25.

    Wang W, Qin H, Zhou L, Ma J. Meta-analysis of the relationship between microRNA-499 rs3746444 polymorphism and hepatocellular carcinoma risk in Asians. J Cancer Res Ther. 2016;12(2):676-80. [PubMed ID: 27461631]. https://doi.org/10.4103/0973-1482.154002.

  • 26.

    Ren YG, Zhou XM, Cui ZG, Hou G. Effects of common polymorphisms in miR-146a and miR-196a2 on lung cancer susceptibility: a meta-analysis. J Thorac Dis. 2016;8(6):1297-305. [PubMed ID: 27293850]. https://doi.org/10.21037/jtd.2016.05.02.

  • 27.

    Liu H, Zhou Y, Liu Q, Xiao G, Wang B, Li W, et al. Association of miR-608 rs4919510 polymorphism and cancer risk: a meta-analysis based on 13,664 subjects. Oncotarget. 2016. [PubMed ID: 27223084]. https://doi.org/10.18632/oncotarget.9509.

  • 28.

    Ji HH, Hong L, Huang GL, Yin HX, Xu P, Luo SY, et al. Association between microRNA-196a2 rs11614913, microRNA-146a rs2910164, and microRNA-423 rs6505162 polymorphisms and esophageal cancer risk: A meta-analysis. Meta Gene. 2015;3:14-25. [PubMed ID: 26925372]. https://doi.org/10.1016/j.mgene.2014.12.001.

  • 29.

    Zhang X, He R, Ren F, Tang R, Chen G. Association of miR-146a rs2910164 polymorphism with squamous cell carcinoma risk: a meta-analysis. J BUON. 2015;20(3):829-41. [PubMed ID: 26214637].

  • 30.

    Zhang P, Wang J, Lu T, Wang X, Zheng Y, Guo S, et al. miR-449b rs10061133 and miR-4293 rs12220909 polymorphisms are associated with decreased esophageal squamous cell carcinoma in a Chinese population. Tumour Biol. 2015;36(11):8789-95. [PubMed ID: 26055141]. https://doi.org/10.1007/s13277-015-3422-2.

  • 31.

    Huo L, Wang Y, Gong Y, Krishnamurthy S, Wang J, Diao L, et al. MicroRNA expression profiling identifies decreased expression of miR-205 in inflammatory breast cancer. Mod Pathol. 2016;29(4):330-46. [PubMed ID: 26916073]. https://doi.org/10.1038/modpathol.2016.38.

  • 32.

    Benderska N, Dittrich AL, Knaup S, Rau TT, Neufert C, Wach S, et al. miRNA-26b Overexpression in Ulcerative Colitis-associated Carcinogenesis. Inflamm Bowel Dis. 2015;21(9):2039-51. [PubMed ID: 26083618]. https://doi.org/10.1097/MIB.0000000000000453.

  • 33.

    Qiu X, Zhu H, Liu S, Tao G, Jin J, Chu H, et al. Expression and prognostic value of microRNA-26a and microRNA-148a in gastric cancer. J Gastroenterol Hepatol. 2016. [PubMed ID: 27529338]. https://doi.org/10.1111/jgh.13533.

  • 34.

    Chen Z, Liu H, Jin W, Ding Z, Zheng S, Yu Y. Tissue microRNA-21 expression predicted recurrence and poor survival in patients with colorectal cancer - a meta-analysis. Onco Targets Ther. 2016;9:2615-24. [PubMed ID: 27226723]. https://doi.org/10.2147/OTT.S103893.

  • 35.

    Li C, Sun J, Xiang Q, Liang Y, Zhao N, Zhang Z, et al. Prognostic role of microRNA-21 expression in gliomas: a meta-analysis. J Neurooncol. 2016. [PubMed ID: 27531352]. https://doi.org/10.1007/s11060-016-2233-7.

  • 36.

    Liang Y, Yang W, Zhu Y, Yuan Y. Prognostic role of microRNA-203 in various carcinomas: evidence from a meta-analysis involving 13 studies. Springerplus. 2016;5(1):1538. [PubMed ID: 27652111]. https://doi.org/10.1186/s40064-016-3225-y.

  • 37.

    Duan F, Wang K, Dai L, Zhao X, Feng Y, Song C, et al. Prognostic significance of low microRNA-218 expression in patients with different types of cancer: Evidence from published studies. Medicine (Baltimore). 2016;95(37):4773. [PubMed ID: 27631228]. https://doi.org/10.1097/MD.0000000000004773.

  • 38.

    Boro A, Bauer D, Born W, Fuchs B. Plasma levels of miRNA-155 as a powerful diagnostic marker for dedifferentiated liposarcoma. Am J Cancer Res. 2016;6(2):544-52. [PubMed ID: 27186423].

  • 39.

    Wang X, Ning Y, Yang L, Liu H, Wu C, Wang S, et al. Diagnostic value of circulating microRNAs for osteosarcoma in Asian populations: a meta-analysis. Clin Exp Med. 2016. [PubMed ID: 27106278]. https://doi.org/10.1007/s10238-016-0422-5.

  • 40.

    Dai S, Lu Y, Long Y, Lai Y, Du P, Ding N, et al. Prognostic value of microRNAs in cervical carcinoma: a systematic review and meta-analysis. Oncotarget. 2016;7(23):35369-78. [PubMed ID: 27177085]. https://doi.org/10.18632/oncotarget.9294.

  • 41.

    Shi C, Zhang Z. The prognostic value of the miR-200 family in ovarian cancer: a meta-analysis. Acta Obstet Gynecol Scand. 2016;95(5):505-12. [PubMed ID: 26910180]. https://doi.org/10.1111/aogs.12883.

  • 42.

    Wang N, Chen P, Huang LP, Wang TZ. Prognostic significance of microRNA-10b overexpression in breast cancer: a meta-analysis. Genet Mol Res. 2016;15(2). [PubMed ID: 27173192]. https://doi.org/10.4238/gmr.15027350.