Skip to main content

Advertisement

Log in

MicroRNA function in cancer: oncogene or a tumor suppressor?

  • NON-THEMATIC REVIEW
  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

MicroRNAs (miRNAs) are small noncoding, double-stranded RNA molecules that can mediate the expression of target genes with complementary sequences. About 5,300 human genes have been implicated as targets for miRNAs, making them one of the most abundant classes of regulatory genes in humans. MiRNAs recognize their target mRNAs based on sequence complementarity and act on them to cause the inhibition of protein translation by degradation of mRNA. Besides contributing to development and normal function, microRNAs have functions in various human diseases. Given the importance of miRNAs in regulating cellular differentiation and proliferation, it is not surprising that their misregulation is linked to cancer. In cancer, miRNAs function as regulatory molecules, acting as oncogenes or tumor suppressors. Amplification or overexpression of miRNAs can down-regulate tumor suppressors or other genes involved in cell differentiation, thereby contributing to tumor formation by stimulating proliferation, angiogenesis, and invasion; i.e., they act as oncogenes. Similarly, miRNAs can down-regulate different proteins with oncogenic activity; i.e., they act as tumor suppressors. This review will highlight the recent discoveries regarding miRNAs and their importance in cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Lewis, B. P., Burge, C. B., & Bartel, D. P. (2005). Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell, 120(1), 15–20.

    Article  CAS  PubMed  Google Scholar 

  2. Rajewsky, N. (2006). microRNA target predictions in animals. Nature Genetics, 38(Suppl), S8–S13.

    Article  CAS  PubMed  Google Scholar 

  3. Lee, R. C., Feinbaum, R. L., & Ambros, V. (1993). The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell, 75(5), 843–854.

    Article  CAS  PubMed  Google Scholar 

  4. Reinhart, B. J., et al. (2000). The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature, 403(6772), 901–906.

    Article  CAS  PubMed  Google Scholar 

  5. Pasquinelli, A. E., et al. (2000). Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature, 408(6808), 86–89.

    Article  CAS  PubMed  Google Scholar 

  6. Lagos-Quintana, M., et al. (2001). Identification of novel genes coding for small expressed RNAs. Science, 294(5543), 853–858.

    Article  CAS  PubMed  Google Scholar 

  7. Lau, N. C., et al. (2001). An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science, 294(5543), 858–862.

    Article  CAS  PubMed  Google Scholar 

  8. Lee, R. C., & Ambros, V. (2001). An extensive class of small RNAs in Caenorhabditis elegans. Science, 294(5543), 862–864.

    Article  CAS  PubMed  Google Scholar 

  9. ALTMAN, L.K., 5 Pioneering Scientists Win Lasker Medical Prizes in New York Times. 2008

  10. Bagga, S., et al. (2005). Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell, 122(4), 553–563.

    Article  CAS  PubMed  Google Scholar 

  11. Pillai, R. S. (2005). MicroRNA function: multiple mechanisms for a tiny RNA? RNA, 11(12), 1753–1761.

    Article  CAS  PubMed  Google Scholar 

  12. Bernstein, E., et al. (2003). Dicer is essential for mouse development. Nature Genetics, 35(3), 215–217.

    Article  CAS  PubMed  Google Scholar 

  13. Harris, K. S., et al. (2006). Dicer function is essential for lung epithelium morphogenesis. Proceedings of the National Academy of Sciences of the United States of America, 103(7), 2208–2213.

    Article  CAS  PubMed  Google Scholar 

  14. Harfe, B. D., et al. (2005). The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb. Proceedings of the National Academy of Sciences of the United States of America, 102(31), 10898–10903.

    Article  CAS  PubMed  Google Scholar 

  15. O'Rourke, J. R., et al. (2007). Essential role for Dicer during skeletal muscle development. Developmental Biology, 311(2), 359–368.

    Article  PubMed  Google Scholar 

  16. Muljo, S. A., et al. (2005). Aberrant T cell differentiation in the absence of Dicer. Journal of Experimental Medicine, 202(2), 261–269.

    Article  CAS  PubMed  Google Scholar 

  17. Yi, R., et al. (2008). A skin microRNA promotes differentiation by repressing ‘stemness’. Nature, 452(7184), 225–229.

    Article  CAS  PubMed  Google Scholar 

  18. Ashraf, S. I., & Kunes, S. (2006). A trace of silence: memory and microRNA at the synapse. Current Opinion in Neurobiology, 16(5), 535–539.

    Article  CAS  PubMed  Google Scholar 

  19. Poy, M. N., et al. (2004). A pancreatic islet-specific microRNA regulates insulin secretion. Nature, 432(7014), 226–230.

    Article  CAS  PubMed  Google Scholar 

  20. Esau, C., et al. (2006). miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metabolic, 3(2), 87–98.

    Article  CAS  Google Scholar 

  21. Esau, C. C., & Monia, B. P. (2007). Therapeutic potential for microRNAs. Advanced drug delivery reviews, 59(2–3), 101–114.

    Article  CAS  PubMed  Google Scholar 

  22. Care, A., et al. (2007). MicroRNA-133 controls cardiac hypertrophy. Nature Medicine, 13(5), 613–618.

    Article  CAS  PubMed  Google Scholar 

  23. Xiao, C., & Rajewsky, K. (2009). MicroRNA control in the immune system: basic principles. Cell, 136(1), 26–36.

    Article  CAS  PubMed  Google Scholar 

  24. Cameron, J. E., et al. (2008). Epstein-Barr virus latent membrane protein 1 induces cellular MicroRNA miR-146a, a modulator of lymphocyte signaling pathways. Journal of Virology, 82(4), 1946–1958.

    Article  CAS  PubMed  Google Scholar 

  25. Gottwein, E., et al. (2007). A viral microRNA functions as an orthologue of cellular miR-155. Nature, 450(7172), 1096–1099.

    Article  CAS  PubMed  Google Scholar 

  26. Moschos, S. A., et al. (2007). Expression profiling in vivo demonstrates rapid changes in lung microRNA levels following lipopolysaccharide-induced inflammation but not in the anti-inflammatory action of glucocorticoids. BMC Genomics, 8, 240.

    Article  PubMed  Google Scholar 

  27. Sonkoly, E., Stahle, M., & Pivarcsi, A. (2008). MicroRNAs and immunity: novel players in the regulation of normal immune function and inflammation. Seminars in Cancer Biology, 18(2), 131–140.

    Article  CAS  PubMed  Google Scholar 

  28. Calin, G. A., et al. (2002). Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America, 99(24), 15524–15529.

    Article  CAS  PubMed  Google Scholar 

  29. Jiang, J., et al. (2005). Real-time expression profiling of microRNA precursors in human cancer cell lines. Nucleic Acids Research, 33(17), 5394–5403.

    Article  CAS  PubMed  Google Scholar 

  30. Davison, T. S., Johnson, C. D., & Andruss, B. F. (2006). Analyzing micro-RNA expression using microarrays. Methods in Enzymology, 411, 14–34.

    Article  CAS  PubMed  Google Scholar 

  31. Liang, Z., et al. (2007). Blockade of invasion and metastasis of breast cancer cells via targeting CXCR4 with an artificial microRNA. Biochemical and Biophysical Research Communications, 363(3), 542–546.

    Article  CAS  PubMed  Google Scholar 

  32. Miska, E. A. (2005). How microRNAs control cell division, differentiation and death. Current Opinion in Genetics and Development, 15(5), 563–568.

    Article  CAS  PubMed  Google Scholar 

  33. Lee, Y. S., et al. (2005). Depletion of human micro-RNA miR-125b reveals that it is critical for the proliferation of differentiated cells but not for the down-regulation of putative targets during differentiation. Journal of Biological Chemistry, 280(17), 16635–16641.

    Article  CAS  PubMed  Google Scholar 

  34. Roldo, C., et al. (2006). MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. Journal of Clinical Oncology, 24(29), 4677–4684.

    Article  CAS  PubMed  Google Scholar 

  35. Dillhoff, M., et al. (2008). MicroRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival. Journal of Gastrointestinal Surgery, 12(12), 2171–2176.

    Article  PubMed  Google Scholar 

  36. Gironella, M., et al. (2007). Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proceedings of the National Academy of Sciences of the United States of America, 104(41), 16170–16175.

    Article  CAS  PubMed  Google Scholar 

  37. Burk, U., et al. (2008). A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Reports, 9(6), 582–589.

    Article  CAS  PubMed  Google Scholar 

  38. Nakajima, G., et al. (2006). Non-coding microRNAs hsa-let-7g and hsa-miR-181b are associated with Chemoresponse to S-1 in Colon Cancer. Cancer Genomics Proteomics, 3(5), 317–324.

    CAS  PubMed  Google Scholar 

  39. Lanza, G., et al. (2007). mRNA/microRNA gene expression profile in microsatellite unstable colorectal cancer. Molecular Cancer, 6, 54.

    Article  PubMed  Google Scholar 

  40. Asangani, I. A., et al. (2008). MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene, 27(15), 2128–2136.

    Article  CAS  PubMed  Google Scholar 

  41. Hayashita, Y., et al. (2005). A polycistronic microRNA cluster, miR-17–92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Research, 65(21), 9628–9632.

    Article  CAS  PubMed  Google Scholar 

  42. Matsubara, H., et al. (2007). Apoptosis induction by antisense oligonucleotides against miR-17–5p and miR-20a in lung cancers overexpressing miR-17–92. Oncogene, 26(41), 6099–6105.

    Article  CAS  PubMed  Google Scholar 

  43. Chang, T. C., et al. (2007). Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Molecular Cell, 26(5), 745–752.

    Article  CAS  PubMed  Google Scholar 

  44. Lodygin, D., et al. (2008). Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle, 7(16), 2591–2600.

    CAS  PubMed  Google Scholar 

  45. Michael, M. Z., et al. (2003). Reduced accumulation of specific microRNAs in colorectal neoplasia. Molecular Cancer Research, 1(12), 882–891.

    CAS  PubMed  Google Scholar 

  46. Akao, Y., Nakagawa, Y., & Naoe, T. (2006). MicroRNAs 143 and 145 are possible common onco-microRNAs in human cancers. Oncology Reports, 16(4), 845–850.

    CAS  PubMed  Google Scholar 

  47. Shi, B., et al. (2007). Micro RNA 145 targets the insulin receptor substrate-1 and inhibits the growth of colon cancer cells. Journal of Biological Chemistry, 282(45), 32582–32590.

    Article  CAS  PubMed  Google Scholar 

  48. Akao, Y., Nakagawa, Y., & Naoe, T. (2006). Let-7 microRNA functions as a potential growth suppressor in human colon cancer cells. Biological and Pharmaceutical Bulletin, 29(5), 903–906.

    Article  CAS  PubMed  Google Scholar 

  49. Takamizawa, J., et al. (2004). Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Research, 64(11), 3753–3756.

    Article  CAS  PubMed  Google Scholar 

  50. Johnson, S. M., et al. (2005). RAS is regulated by the let-7 microRNA family. Cell, 120(5), 635–647.

    Article  CAS  PubMed  Google Scholar 

  51. Johnson, C. D., et al. (2007). The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Research, 67(16), 7713–7722.

    Article  CAS  PubMed  Google Scholar 

  52. Lee, Y. S., & Dutta, A. (2007). The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes and Development, 21(9), 1025–1030.

    Article  CAS  PubMed  Google Scholar 

  53. Bommer, G. T., et al. (2007). p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Current Biology, 17(15), 1298–1307.

    Article  CAS  PubMed  Google Scholar 

  54. Calin, G. A., & Croce, C. M. (2006). MicroRNA-cancer connection: the beginning of a new tale. Cancer Research, 66(15), 7390–7394.

    Article  CAS  PubMed  Google Scholar 

  55. Cimmino, A., et al. (2005). miR-15 and miR-16 induce apoptosis by targeting BCL2. Proceedings of the National Academy of Sciences of the United States of America, 102(39), 13944–13949.

    Article  CAS  PubMed  Google Scholar 

  56. Lin, T., et al. (2009). MicroRNA-143 as a tumor suppressor for bladder cancer. The Journal of Urology, 181, 1372–1380.

    Article  CAS  PubMed  Google Scholar 

  57. Varambally, S., et al. (2008). Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science, 322(5908), 1695–1699.

    Article  CAS  PubMed  Google Scholar 

  58. Liu, C. G., et al. (2004). An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues. Proceedings of the National Academy of Sciences of the United States of America, 101(26), 9740–9744.

    Article  CAS  PubMed  Google Scholar 

  59. Walsh, T., & King, M. C. (2007). Ten genes for inherited breast cancer. Cancer Cell, 11(2), 103–105.

    Article  CAS  PubMed  Google Scholar 

  60. Xin, F., et al. (2008). Computational analysis of MicroRNA profiles and their target genes suggests significant involvement in breast cancer antiestrogen resistance. Bioinformatics, 25, 430–434.

    Article  PubMed  Google Scholar 

  61. Scott, G. K., et al. (2006). Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Research, 66(3), 1277–1281.

    Article  CAS  PubMed  Google Scholar 

  62. Abdelrahim, M., et al. (2002). Small inhibitory RNA duplexes for Sp1 mRNA block basal and estrogen-induced gene expression and cell cycle progression in MCF-7 breast cancer cells. Journal of Biological Chemistry, 277(32), 28815–28822.

    Article  CAS  PubMed  Google Scholar 

  63. Ma, L., Teruya-Feldstein, J., & Weinberg, R. A. (2007). Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature, 449(7163), 682–688.

    Article  CAS  PubMed  Google Scholar 

  64. Si, M. L., et al. (2007). miR-21-mediated tumor growth. Oncogene, 26(19), 2799–2803.

    Article  CAS  PubMed  Google Scholar 

  65. Zhu, S., et al. (2007). MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). Journal of Biological Chemistry, 282(19), 14328–14336.

    Article  CAS  PubMed  Google Scholar 

  66. Boyd, J., et al. (1995). Regulation of microfilament organization and anchorage-independent growth by tropomyosin 1. Proceedings of the National Academy of Sciences of the United States of America, 92(25), 11534–11538.

    Article  CAS  PubMed  Google Scholar 

  67. Frankel, L. B., et al. (2008). Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. Journal of Biological Chemistry, 283(2), 1026–1033.

    Article  CAS  PubMed  Google Scholar 

  68. Hossain, A., Kuo, M. T., & Saunders, G. F. (2006). Mir-17–5p regulates breast cancer cell proliferation by inhibiting translation of AIB1 mRNA. Molecular and Cellular Biology, 26(21), 8191–8201.

    Article  CAS  PubMed  Google Scholar 

  69. Murray, G. I., et al. (1997). Tumor-specific expression of cytochrome P450 CYP1B1. Cancer Research, 57(14), 3026–3031.

    CAS  PubMed  Google Scholar 

  70. Tsuchiya, Y., et al. (2006). MicroRNA regulates the expression of human cytochrome P450 1B1. Cancer Research, 66(18), 9090–9098.

    Article  CAS  PubMed  Google Scholar 

  71. Mattie, M. D., et al. (2006). Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies. Molecular Cancer, 5, 24.

    Article  PubMed  Google Scholar 

  72. Scott, G. K., et al. (2007). Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b. Journal of Biological Chemistry, 282(2), 1479–1486.

    Article  CAS  PubMed  Google Scholar 

  73. Eger, A., et al. (2005). DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene, 24(14), 2375–2385.

    Article  CAS  PubMed  Google Scholar 

  74. Hurteau, G. J., et al. (2007). Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Research, 67(17), 7972–7976.

    Article  CAS  PubMed  Google Scholar 

  75. Adams, B. D., Furneaux, H., & White, B. A. (2007). 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. Molecular Endocrinology, 21(5), 1132–1147.

    Article  CAS  PubMed  Google Scholar 

  76. Kondo, N., et al. (2008). miR-206 Expression is down-regulated in estrogen receptor alpha-positive human breast cancer. Cancer Research, 68(13), 5004–5008.

    Article  CAS  PubMed  Google Scholar 

  77. Chambers, A. F., Groom, A. C., & MacDonald, I. C. (2002). Dissemination and growth of cancer cells in metastatic sites. Nature Reviews Cancer, 2(8), 563–572.

    Article  CAS  PubMed  Google Scholar 

  78. Fidler, I. J. (2003). The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nature Review Cancer, 3(6), 453–458.

    Article  CAS  Google Scholar 

  79. Huang, Q., et al. (2008). The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nature Cell Biology, 10(2), 202–210.

    Article  CAS  PubMed  Google Scholar 

  80. Tavazoie, S. F., et al. (2008). Endogenous human microRNAs that suppress breast cancer metastasis. Nature, 451(7175), 147–152.

    Article  CAS  PubMed  Google Scholar 

  81. Yu, F., et al. (2007). Let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell, 131(6), 1109–1123.

    Article  CAS  PubMed  Google Scholar 

  82. Gebeshuber, C. A., Zatloukal, K., & Martinez, J. (2009). miR-29a suppresses tristetraprolin, which is a regulator of epithelial polarity and metastasis. EMBO Reports, 10(4), 400–405.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We apologize to all researchers whose work could not be cited in this review as a result of space constraints. This work was supported by NIH RO1 CA 115706, Susan Komen BCTR 0600278, and funds from the Louisiana Cancer Research Consortium to SKA.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Suresh K. Alahari.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shenouda, S.K., Alahari, S.K. MicroRNA function in cancer: oncogene or a tumor suppressor?. Cancer Metastasis Rev 28, 369–378 (2009). https://doi.org/10.1007/s10555-009-9188-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-009-9188-5

Keywords

Navigation