Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

MicroRNA and drug resistance

Cancer Gene Therapy volume 17, pages 523–531 (2010)Cite this article

Subjects

Abstract

Chemotherapy is the preferred treatment for malignancies. However, a successful long-term use of chemotherapy is often prevented by the development of drug resistance. Many mechanisms such as gene mutation, DNA methylation and histone modification have important roles in the resistance of cancer cells to chemotherapeutic agents. Climent suggested miR-125b was involved in the development of drug resistance by microRNA (miRNA) dysregulation. miRNAs are endogenously expressed small non-coding RNAs, which are evolutionarily conserved and function as regulators of gene expression. Much effort has been exerted in analyzing the role of miRNAs in the development of drug resistance in a variety of malignancies. Several research groups have shown that the expressions of miRNAs in chemoresistant cancer cells and their parental chemosensitive ones are different. The molecular targets and mechanisms of chemosensitivity and chemoresistance are also elucidated. This article reviews the functions of miRNAs in the development of drug resistance.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Bartel DP . MiRNAs: genomics, biogenesis, mechanism and function. Cell 2004; 116: 281–297.

    Article  CAS  Google Scholar 

  2. Carrington JC, Ambros V . Role of microRNAs in plant and animal development. Science 2003; 301: 336–338.

    Article  CAS  Google Scholar 

  3. Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T . Identification of novel genes coding for small expressed RNAs. Science 2001; 294: 853–858.

    Article  CAS  Google Scholar 

  4. Perera RJ, Ray A . MicroRNAs in the search for understanding human diseases. Biodrugs 2007; 21: 97–104.

    Article  CAS  Google Scholar 

  5. 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.

    Article  CAS  Google Scholar 

  6. Ambros V . The functions of animal microRNAs. Nature 2004; 431: 350–355.

    Article  CAS  Google Scholar 

  7. Lytle JR, Yario TA, Steitz JA . Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc Natl Acad Sci USA 2007; 104: 9667–9672.

    Article  CAS  Google Scholar 

  8. Vasudevan S, Tong Y, Steitz JA . Switching from repression to activation: microRNAs can up-regulate translation. Science 2007; 318: 1931–1934.

    Article  CAS  Google Scholar 

  9. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D et al. MicroRNA expression profiles classify human cancers. Nature 2005; 435: 834–838.

    Article  CAS  Google Scholar 

  10. Ma L, Teruya-Feldstein J, Weinberg RA . Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 2007; 449: 682–688.

    Article  CAS  Google Scholar 

  11. Burchenal JH, Robinson E, Johnston SF, Kushida MH . The induction of resistance to 4-amino-N10-methylpteroylglutamic acid in a strain of transmitted mouse leukemia. Science 1950; 111: 116.

    Article  CAS  Google Scholar 

  12. Climent J, Dimitrow P, Fridlyand J, Palacios J, Siebert R, Albertson DG et al. Deletion of chromosome 11q predicts response to anthracycline-based chemotherapy in early breast cancer. Cancer Res 2007; 67: 818–826.

    Article  CAS  Google Scholar 

  13. Blower PE, Verducci JS, Lin S, Zhou J, Chung JH, Dai Z et al. MicroRNA expression profiles for the NCI-60 cancer cell panel. Mol Cancer Ther 2007; 6: 1483–1491.

    Article  CAS  Google Scholar 

  14. Miller TE, Ghoshal K, Ramaswamy B, Roy S, Datta J, Shapiro CL et al. MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1. J Biol Chem 2008; 283: 29897–29903.

    Article  CAS  Google Scholar 

  15. le Sage C, Nagel R, Egan DA, Schrier M, Mesman E, Mangiola A et al. Regulation of the p27(kip1) tumor suppressor by miR-221and miR-222 promotes cancer cell proliferation. EMBO J 2007; 26: 3699–3708.

    Article  CAS  Google Scholar 

  16. Xin F, Li M, Balch C, Thomson M, Fan M, Liu Y et al. Computational analysis of microRNA profiles and their target genes suggests significant involvement in breast cancer antiestrogen resistance. Bioinformatics 2009; 25: 430–434.

    Article  CAS  Google Scholar 

  17. Benson JR . Role of transforming growth factor beta in breast carcinogenesis. Lancet Oncol 2004; 5: 229–239.

    Article  CAS  Google Scholar 

  18. Muraoka-Cook RS, Dumont N, Arteaga CL . Dual role of transforming growth factor beta in mammary tumorigenesis and metastatic progression. Clin Cancer Res 2005; 11: 937s–943s.

    CAS  PubMed  Google Scholar 

  19. Fan M, Yan PS, Hartman-Frey C, Chen L, Paik H, Oyer SL et al. Diverse gene expression and DNA methylation profiles correlate with differential adaptation of breast cancer cells to the antiestrogens tamoxifen and fulvestrant. Cancer Res 2006; 66: 11954–11966.

    Article  CAS  Google Scholar 

  20. Giacinti L, Claudio PP, Lopez M, Giordano A . Epigenetic information and estrogen receptor alpha expression in breast cancer. Oncologist 2006; 11: 1–8.

    Article  CAS  Google Scholar 

  21. Zhao JJ, Lin J, Yang H, Kong W, He L, Ma X et al. MicroRNA-221/222 negatively regulates estrogen receptor alpha and is associated with tamoxifen resistance in breast cancer. J Biol Chem 2008; 283: 31079–31086.

    Article  CAS  Google Scholar 

  22. Adams BD, Furneaux H, White BA . The micro-ribonucleic acid (miRNA) miR-206 targets the human estrogen receptor-alpha (ERalpha) and represses ERalpha messenger RNA and protein expression in breast cancer cell lines. Mol Endocrinol 2007; 21: 1132–1147.

    Article  CAS  Google Scholar 

  23. Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY . miR-21-mediated tumor growth. Oncogene 2007; 26: 2799–2803.

    Article  CAS  Google Scholar 

  24. Salter KH, Acharya CR, Walters KS, Redman R, Anguiano A, Garman KS et al. An integrated approach to the prediction of chemotherapeutic response in patients with breast cancer. PLoS One 2008; 3: e1908.

    Article  Google Scholar 

  25. Kovalchuk O, Filkowski J, Meservy J, Ilnytskyy Y, Tryndyak VP, Chekhun VF et al. Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol Cancer Ther 2008; 7: 2152–2159.

    Article  CAS  Google Scholar 

  26. Chen YN, Mickley LA, Schwartz AM, Acton EM, Hwang JL, Fojo AT . Characterization of adriamycin-resistant human breast cancer cells which display overexpression of a novel resistance-related membrane protein. J Biol Chem 1990; 265: 10073–10080.

    CAS  PubMed  Google Scholar 

  27. Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA 1998; 95: 15665–15670.

    Article  CAS  Google Scholar 

  28. Chen GQ, Zhao ZW, Zhou HY, Liu YJ, Yang HJ . Systematic analysis of microRNA involved in resistance of the MCF-7 human breast cancer cell to doxorubicin. Med Oncol 2 May 2009; [Epub ahead of print].

  29. Pan YZ, Morris ME, Yu AM . MicroRNA-328 negatively regulates the expression of breast cancer resistance protein (BCRP/ABCG2) in human cancer cells. Mol Pharmacol 2009; 75: 1374–1379.

    Article  CAS  Google Scholar 

  30. Al-Hajj M . Cancer stem cells and oncology therapeutics. Curr Opin Oncol 2007; 19: 61–64.

    PubMed  Google Scholar 

  31. Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 2007; 131: 1109–1123.

    Article  CAS  Google Scholar 

  32. Yang H, Kong W, He L, Zhao JJ, O’Donnell JD, Wang J et al. MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res 2008; 68: 425–433.

    Article  CAS  Google Scholar 

  33. Yang N, Kaur S, Volinia S, Greshock J, Lassus H, Hasegawa K et al. MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancer. Cancer Res 2008; 68: 10307–10314.

    Article  CAS  Google Scholar 

  34. Sorrentino A, Liu CG, Addario A, Peschle C, Scambia G, Ferlini C . Role of microRNAs in drug-resistant ovarian cancer cells. Gynecol Oncol 2008; 111: 478–486.

    Article  CAS  Google Scholar 

  35. Paulus P, Stanley ER, Schäfer R, Abraham D, Aharinejad S . Colony-stimulating factor-1 antibody reverses chemoresistance in human MCF-7 breast cancer xenografts. Cancer Res 2006; 66: 4349–4356.

    Article  CAS  Google Scholar 

  36. Zhu H, Wu H, Liu X, Evans BR, Medina DJ, Liu CG et al. Role of microRNA miR-27a and miR-451 in the regulation of MDR1/P-glycoprotein expression in human cancer cells. Biochem Pharmacol 2008; 76: 582–588.

    Article  CAS  Google Scholar 

  37. Blower PE, Chung JH, Verducci JS, Lin S, Park JK, Dai Z et al. MicroRNAs modulate the chemosensitivity of tumor cells. Mol Cancer Ther 2008; 7: 1–9.

    Article  CAS  Google Scholar 

  38. Schaefer U, Voloshanenko O, Willen D, Walczak H . TRAIL: a multifunctional cytokine. Front Biosci 2007; 12: 3813–3824.

    Article  CAS  Google Scholar 

  39. Falschlehner C, Emmerich CH, Gerlach B, Walczak H . TRAIL signalling: decisions between life and death. Int J Biochem Cell Biol 2007; 39: 1462–1475.

    Article  CAS  Google Scholar 

  40. Garofalo M, Quintavalle C, Di Leva G, Zanca C, Romano G, Taccioli C et al. MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer. Oncogene 2008; 27: 3845–3855.

    Article  CAS  Google Scholar 

  41. Felli N, Fontana L, Pelosi E, Botta R, Bonci D, Facchiano F et al. MiRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proc Natl Acad Sci USA 2005; 102: 18081–18086.

    Article  CAS  Google Scholar 

  42. He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, Volinia S et al. The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci USA 2005; 102: 19075–19080.

    Article  CAS  Google Scholar 

  43. Poliseno L, Tuccoli A, Mariani L, Evangelista M, Citti L, Woods K et al. MicroRNAs modulate the angiogenic properties of HUVECs. Blood 2006; 108: 3068–3071.

    Article  CAS  Google Scholar 

  44. Fujita Y, Kojima K, Hamada N, Ohhashi R, Akao Y, Nozawa Y et al. Effects of miR-34a on cell growth and chemoresistance in prostate cancer PC3 cells. Biochem Biophys Res Commun 2008; 377: 114–119.

    Article  CAS  Google Scholar 

  45. Kojima K, Ohhashi R, Fujita Y, Hamada N, Akao Y, Nozawa Y et al. A role for SIRT1 in cell growth and chemoresistance in prostate cancer PC3 and DU145 cells. Biochem Biophys Res Commun 2008; 373: 423–428.

    Article  CAS  Google Scholar 

  46. Chu F, Chou PM, Zheng X, Mirkin BL, Rebbaa A . Control of multidrug resistance gene mdr1 and cancer resistance to chemotherapy by the longevity gene sirt1. Cancer Res 2005; 65: 10183–10187.

    Article  CAS  Google Scholar 

  47. Yamakuchi M, Ferlito M, Lowenstein CJ . miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci USA 2008; 105: 13421–13426.

    Article  CAS  Google Scholar 

  48. Johnson DG, Ohtani K, Nevins JR . Autoregulatory control of E2F1 expression in response to positive and negative regulators of cell cycle progression. Genes Dev 1994; 8: 1514–1525.

    Article  CAS  Google Scholar 

  49. Wang C, Chen L, Hou X, Li Z, Kabra N, Ma Y et al. Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. Nat Cell Biol 2006; 8: 1025–1031.

    Article  CAS  Google Scholar 

  50. Tong AW, Fulgham P, Jay C, Chen P, Khalil I, Liu S et al. MicroRNA profile analysis of human prostate cancers. Cancer Gene Ther 2009; 16: 206–216.

    Article  CAS  Google Scholar 

  51. Fan D, Zhang X, Chen X, Mou Z, Hu J, Zhou S et al. Bird's-eye view on gastric cancer research of the past 25 years. J Gastroenterol Hepatol 2005; 20: 360–365.

    Article  Google Scholar 

  52. Xia L, Zhang D, Du R, Pan Y, Zhao L et al. miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. Int J Cancer 2008; 123: 372–379.

    Article  CAS  Google Scholar 

  53. Reed JC . Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistance. Curr Opin Oncol 1995; 7: 541–546.

    Article  CAS  Google Scholar 

  54. Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 2007; 26: 745–752.

    Article  CAS  Google Scholar 

  55. Bommer GT, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, Love RE et al. p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr Biol 2007; 17: 1298–1307.

    Article  CAS  Google Scholar 

  56. Corney DC, Flesken-Nikitin A, Godwin AK, Wang W, Nikitin AY . MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth. Cancer Res 2007; 67: 8433–8438.

    Article  CAS  Google Scholar 

  57. Ji Q, Hao X, Meng Y, Zhang M, Desano J, Fan D et al. Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres. BMC Cancer 2008; 8: 266.

    Article  Google Scholar 

  58. To KK, Zhan Z, Litman T, Bates SE . Regulation of ABCG2 expression at the 3′ untranslated region of its mRNA through modulation of transcript Ssability and protein translation by a putative microRNA in the S1 colon cancer cell line. Mol Cell Biol 2008; 28: 5147–5161.

    Article  CAS  Google Scholar 

  59. Liao R, Sun J, Zhang L, Lou G, Chen M, Zhou D et al. MicroRNAs play a role in the development of human hematopoietic stem cells. J Cell Biochem 2008; 104: 805–817.

    Article  CAS  Google Scholar 

  60. Nakajima G, Hayashi K, Xi Y, Kudo K, Uchida K, Takasaki K et al. Non-coding microRNAs hsa-let-7g and hsa-miR-181b are associated with chemoresponse to S-1 in colon cancer. Cancer Genomics Proteomics 2006; 3: 317–324.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Tsang WP, Kwok TT . Let-7a microRNA suppresses therapeutics-induced cancer cell death by targeting caspase-3. Apoptosis 2008; 13: 1215–1222.

    Article  CAS  Google Scholar 

  62. Frassanito MA, Cusmai A, Iodice G, Dammacco F . Autocrine interleukin-6 production and highly malignant multiple myeloma: relation with resistance to drug-induced apoptosis. Blood 2001; 97: 483–489.

    Article  CAS  Google Scholar 

  63. Hodge DR, Hurt EM, Farrar WL . The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 2005; 41: 2502–2512.

    Article  CAS  Google Scholar 

  64. Meng F, Henson R, Wehbe-Janek H, Smith H, Ueno Y, Patel T . The microRNA let-7a modulates interleukin-6-dependent STAT-3 survival signaling in malignant human cholangiocytes. J Biol Chem 2007; 282: 8256–8264.

    Article  CAS  Google Scholar 

  65. Meng F, Henson R, Lang M, Wehbe H, Maheshwari S, Mendell JT et al. Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology 2006; 130: 2113–2129.

    Article  CAS  Google Scholar 

  66. Taniai M, Grambihler A, Higuchi H, Werneburg N, Bronk SF, Farrugia DJ et al. Mcl-1 mediates tumor necrosis factor-related apoptosis-inducing ligand resistance in human cholangiocarcinoma cells. Cancer Res 2004; 64: 3517–3524.

    Article  CAS  Google Scholar 

  67. Mott JL, Kobayashi S, Bronk SF, Gores GJ . mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene 2007; 26: 6133–6140.

    Article  CAS  Google Scholar 

  68. Lee Y, Kim M, Han J, Yeom KH, Lee S, Baek SH et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J 2004; 23: 4051–4060.

    Article  CAS  Google Scholar 

  69. Fontana L, Fiori ME, Albini S, Cifaldi L, Giovinazzi S, Forloni M et al. Antagomir-17-5p abolishes the growth of therapy-resistant neuroblastoma through p21 and BIM. PLoS One 2008; 3: e2236.

    Article  Google Scholar 

  70. Döhner H, Fischer K, Bentz M, Hansen K, Benner A, Cabot G et al. p53 Gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 1995; 85: 1580–1589.

    PubMed  Google Scholar 

  71. Zenz T, Mohr J, Eldering E, Kater AP, Bühler A, Kienle D et al. miR-34a as part of the resistance network in chronic lymphocytic leukemia. Blood 2009; 113: 3801–3808.

    Article  CAS  Google Scholar 

  72. Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE et al. A microRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 2005; 353: 1793–1801.

    Article  CAS  Google Scholar 

  73. Calin GA, Croce CM . MicroRNA signatures in human cancers. Nat Rev Cancer 2006; 6: 857–866.

    Article  CAS  Google Scholar 

  74. Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 2005; 102: 13944–13949.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology, Qilu Hospital, Shandong University, Jinan, Shandong, China,

    J Ma, C Dong & C Ji

Authors
  1. J Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Ji.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ma, J., Dong, C. & Ji, C. MicroRNA and drug resistance. Cancer Gene Ther 17, 523–531 (2010). https://doi.org/10.1038/cgt.2010.18

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2010.18

Keywords

This article is cited by

Search

Advanced search

Quick links