Tumor Biology

, Volume 37, Issue 1, pp 177–183 | Cite as

Aberrant regulation of miR-15b in human malignant tumors and its effects on the hallmarks of cancer

  • Ci Zhao
  • Guanyu Wang
  • Yuanyuan Zhu
  • Xiaobo Li
  • Feihu Yan
  • Chunhui Zhang
  • Xiaoyi Huang
  • Yanqiao Zhang
Review

Abstract

MicroRNAs encoded by the miR-15b/16-2 cluster act as tumor suppressors. Aberrant regulation of miR-15b in human malignant tumors is reportedly involved in cancer development, contributing to cell death, reduced proliferation, angiogenesis and metastasis resistance, metabolism reprogramming, genome instability, and tumor-associated inflammation. In this review, we summarize the mechanisms involved in regulating miR-15b expression in mammalian tumors and discuss the effects of miR-15b dysregulation on the hallmarks of cancer and highlight its role as a potentially valuable target for future cancer therapeutic strategies.

Keywords

MicroRNAs MiR-15b Angiogenesis and metastasis Metabolism 

Notes

Acknowledgments

This work is supported by the National Natural Science Foundation of China (No. 81172265), Supporting Certificated of Heilongjiang Postdoctoral Scientific Research Developmental Fund (No. LBH-Q14108), and Start Funding of The Affiliated Tumour Hospital of Harbin Medical University (No.YRC2014-01).

Conflicts of interest

None.

References

  1. 1.
    Yue J, Tigyi G. Conservation of mir-15a/16-1 and mir-15b/16-2 clusters. Mamm Genome. 2010;21:88–94.CrossRefPubMedGoogle Scholar
  2. 2.
    Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of microRNA genes mir15 and mir16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002;99:15524–9.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Kim YK, Kim VN. Processing of intronic microRNAs. EMBO J. 2007;26:775–83.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Kim VN, Han J, Siomi MC. Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol. 2009;10:126–39.CrossRefPubMedGoogle Scholar
  5. 5.
    Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB. Prediction of mammalian microRNA targets. Cell. 2003;115:787–98.CrossRefPubMedGoogle Scholar
  6. 6.
    Graves P, Zeng Y. Biogenesis of mammalian microRNAs: a global view. Genomics Proteomics Bioinformatics. 2012;10:239–45.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Myklebust MP, Bruland O, Fluge O, Skarstein A, Balteskard L, Dahl O. MicroRNA-15b is induced with e2f-controlled genes in hpv-related cancer. Br J Cancer. 2011;105:1719–25.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ofir M, Hacohen D, Ginsberg D. Mir-15 and mir-16 are direct transcriptional targets of e2f1 that limit e2f-induced proliferation by targeting cyclin E. Mol Cancer Res. 2011;9:440–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Bueno MJ, Gomez de Cedron M, Laresgoiti U, Fernandez-Piqueras J, Zubiaga AM, Malumbres M. Multiple e2f-induced microRNAs prevent replicative stress in response to mitogenic signaling. Mol Cell Biol. 2010;30:2983–95.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Subhawong AP, Subhawong T, Nassar H, Kouprina N, Begum S, Vang R, et al. Most basal-like breast carcinomas demonstrate the same rb-/p16+ immunophenotype as the hpv-related poorly differentiated squamous cell carcinomas which they resemble morphologically. Am J Surg Pathol. 2009;33:163–75.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Dick FA, Rubin SM. Molecular mechanisms underlying rb protein function. Nat Rev Mol Cell Biol. 2013;14:297–306.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Liu X, Gu X, Sun L, Flowers AB, Rademaker AW, Zhou Y, et al. Downregulation of smurf2, a tumor-suppressive ubiquitin ligase, in triple-negative breast cancers: Involvement of the rb-microRNA axis. BMC Cancer. 2014;14:57.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wilting SM, Snijders PJ, Verlaat W, Jaspers A, van de Wiel MA, van Wieringen WN, et al. Altered microRNA expression associated with chromosomal changes contributes to cervical carcinogenesis. Oncogene. 2013;32:106–16.CrossRefPubMedGoogle Scholar
  14. 14.
    Rahman M, Lovat F, Romano G, Calore F, Acunzo M, Bell EH, et al. Mir-15b/16-2 regulates factors that promote p53 phosphorylation and augments the DNA damage response following radiation in the lung. J Biol Chem. 2014;289:26406–16.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Li G, Miskimen KL, Wang Z, Xie XY, Brenzovich J, Ryan JJ, et al. Stat5 requires the n-domain for suppression of mir15/16, induction of bcl-2, and survival signaling in myeloproliferative disease. Blood. 2010;115:1416–24.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Liu J, Yang L, Zhang J, Zhang J, Chen Y, Li K, et al. Knock-down of ndrg2 sensitizes cervical cancer hela cells to cisplatin through suppressing bcl-2 expression. BMC Cancer. 2012;12:370.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Polytarchou C, Iliopoulos D, Struhl K. An integrated transcriptional regulatory circuit that reinforces the breast cancer stem cell state. Proc Natl Acad Sci U S A. 2012;109:14470–5.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Qian S, Ding JY, Xie R, An JH, Ao XJ, Zhao ZG, et al. MicroRNA expression profile of bronchioalveolar stem cells from mouse lung. Biochem Biophys Res Commun. 2008;377:668–73.CrossRefPubMedGoogle Scholar
  19. 19.
    Cory S, Adams JM. The bcl2 family: Regulators of the cellular life-or-death switch. Nat Rev Cancer. 2002;2:647–56.CrossRefPubMedGoogle Scholar
  20. 20.
    Xia L, Zhang D, Du R, Pan Y, Zhao L, Sun S, et al. Mir-15b and mir-16 modulate multidrug resistance by targeting bcl2 in human gastric cancer cells. Int J Cancer. 2008;123:372–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Chung GE, Yoon JH, Myung SJ, Lee JH, Lee SH, Lee SM, et al. High expression of microrna-15b predicts a low risk of tumor recurrence following curative resection of hepatocellular carcinoma. Oncol Rep. 2010;23(1):113–9.PubMedGoogle Scholar
  22. 22.
    Sun H, Meng X, Han J, Zhang Z, Wang B, Bai X, et al. Anti-cancer activity of dha on gastric cancer—an in vitro and in vivo study. Tumour Biol. 2013;34:3791–800.CrossRefPubMedGoogle Scholar
  23. 23.
    Shen J, Wan R, Hu G, Yang L, Xiong J, Wang F, et al. Mir-15b and mir-16 induce the apoptosis of rat activated pancreatic stellate cells by targeting bcl-2 in vitro. Pancreatology. 2012;12:91–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Fleming NH, Zhong J, da Silva IP, Vega-Saenz de Miera E, Brady B, Han SW, et al. Serum-based miRNAs in the prediction and detection of recurrence in melanoma patients. Cancer. 2015;121:51–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Xia H, Qi Y, Ng SS, Chen X, Chen S, Fang M, et al. MicroRNA-15b regulates cell cycle progression by targeting cyclins in glioma cells. Biochem Biophys Res Commun. 2009;380:205–10.CrossRefPubMedGoogle Scholar
  26. 26.
    Sun G, Shi L, Yan S, Wan Z, Jiang N, Fu L, et al. Mir-15b targets cyclin d1 to regulate proliferation and apoptosis in glioma cells. Biomed Res Int. 2014;2014:687826.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Kamat AA, Merritt WM, Coffey D, Lin YG, Patel PR, Broaddus R, et al. Clinical and biological significance of vascular endothelial growth factor in endometrial cancer. Clin Cancer Res. 2007;13:7487–95.CrossRefPubMedGoogle Scholar
  28. 28.
    Chan LS, Yue PY, Wong YY, Wong RN. Microrna-15b contributes to ginsenoside-rg1-induced angiogenesis through increased expression of vegfr-2. Biochem Pharmacol. 2013;86:392–400.CrossRefPubMedGoogle Scholar
  29. 29.
    Zheng X, Chopp M, Lu Y, Buller B, Jiang F. Mir-15b and mir-152 reduce glioma cell invasion and angiogenesis via nrp-2 and mmp-3. Cancer Lett. 2013;329:146–54.CrossRefPubMedGoogle Scholar
  30. 30.
    Geretti E, Klagsbrun M. Neuropilins: Novel targets for anti-angiogenesis therapies. Cell Adh Migr. 2007;1:56–61.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Liu Z, Yang D, Xie P, Ren G, Sun G, Zeng X, et al. Mir-106b and mir-15b modulate apoptosis and angiogenesis in myocardial infarction. Cell Physiol Biochem. 2012;29:851–62.CrossRefPubMedGoogle Scholar
  32. 32.
    Karaa ZS, Iacovoni JS, Bastide A, Lacazette E, Touriol C, Prats H. The vegf ireses are differentially susceptible to translation inhibition by mir-16. RNA. 2009;15:249–54.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Pescador N, Perez-Barba M, Ibarra JM, Corbaton A, Martinez-Larrad MT, Serrano-Rios M. Serum circulating microRNA profiling for identification of potential type 2 diabetes and obesity biomarkers. PLoS One. 2013;8, e77251.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ye EA, Steinle JJ. Mir-15b/16 protects primary human retinal microvascular endothelial cells against hyperglycemia-induced increases in tumor necrosis factor alpha and suppressor of cytokine signaling 3. J Neuroinflammation. 2015;12:44.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Zhang Y, Cheng X, Lu Z, Wang J, Chen H, Fan W, et al. Upregulation of mir-15b in nafld models and in the serum of patients with fatty liver disease. Diabetes Res Clin Pract. 2013;99:327–34.CrossRefPubMedGoogle Scholar
  36. 36.
    Davidson LA, Wang N, Shah MS, Lupton JR, Ivanov I, Chapkin RS. N-3 polyunsaturated fatty acids modulate carcinogen-directed non-coding microRNA signatures in rat colon. Carcinogenesis. 2009;30:2077–84.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Nishi H, Ono K, Iwanaga Y, Horie T, Nagao K, Takemura G, et al. MicroRNA-15b modulates cellular atp levels and degenerates mitochondria via arl2 in neonatal rat cardiac myocytes. J Biol Chem. 2010;285:4920–30.CrossRefPubMedGoogle Scholar
  38. 38.
    Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Favreau AJ, Sathyanarayana P. Mir-590-5p, mir-219-5p, mir-15b and mir-628-5p are commonly regulated by il-3, gm-csf and g-csf in acute myeloid leukemia. Leuk Res. 2012;36:334–41.CrossRefPubMedGoogle Scholar
  40. 40.
    Baraniskin A, Kuhnhenn J, Schlegel U, Maghnouj A, Zollner H, Schmiegel W, et al. Identification of microRNAs in the cerebrospinal fluid as biomarker for the diagnosis of glioma. Neuro Oncol. 2012;14:29–33.CrossRefPubMedGoogle Scholar
  41. 41.
    Liu AM, Yao TJ, Wang W, Wong KF, Lee NP, Fan ST, et al. Circulating mir-15b and mir-130b in serum as potential markers for detecting hepatocellular carcinoma: a retrospective cohort study. BMJ Open. 2012;2, e000825.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Jiang X, Du L, Wang L, Li J, Liu Y, Zheng G, et al. Serum microRNA expression signatures identified from genome-wide microRNA profiling serve as novel noninvasive biomarkers for diagnosis and recurrence of bladder cancer. Int J Cancer. 2015;136:854–62.CrossRefPubMedGoogle Scholar
  43. 43.
    Komatsu S, Ichikawa D, Hirajima S, Kawaguchi T, Miyamae M, Okajima W, et al. Plasma microRNA profiles: Identification of mir-25 as a novel diagnostic and monitoring biomarker in oesophageal squamous cell carcinoma. Br J Cancer. 2014;111:1614–24.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Satzger I, Mattern A, Kuettler U, Weinspach D, Voelker B, Kapp A, et al. MicroRNA-15b represents an independent prognostic parameter and is correlated with tumor cell proliferation and apoptosis in malignant melanoma. Int J Cancer. 2010;126:2553–62.PubMedGoogle Scholar
  45. 45.
    Aslam MI, Venkatesh J, Jameson JS, West K, Pringle JH, Singh B. MicroRNA expression profiling based identification of high risk dukes' stage b colorectal cancer: a preliminary study. Colorectal Dis. 2014.Google Scholar
  46. 46.
    Medina-Villaamil V, Martinez-Breijo S, Portela-Pereira P, Quindos-Varela M, Santamarina-Cainzos I, Anton-Aparicio LM, et al. Circulating microRNAs in blood of patients with prostate cancer. Actas Urol Esp. 2014;38:633–9.CrossRefPubMedGoogle Scholar
  47. 47.
    Wang L, Zhu MJ, Ren AM, Wu HF, Han WM, Tan RY, et al. A ten-microRNA signature identified from a genome-wide microRNA expression profiling in human epithelial ovarian cancer. PLoS One. 2014;9, e96472.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Huang YH, Lin KH, Chen HC, Chang ML, Hsu CW, Lai MW, et al. Identification of postoperative prognostic microRNA predictors in hepatocellular carcinoma. PLoS One. 2012;7, e37188.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Hennessey PT, Sanford T, Choudhary A, Mydlarz WW, Brown D, Adai AT, et al. Serum microRNA biomarkers for detection of non-small cell lung cancer. PLoS One. 2012;7, e32307.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Jones KB, Salah Z, Del Mare S, Galasso M, Gaudio E, Nuovo GJ, et al. Mirna signatures associate with pathogenesis and progression of osteosarcoma. Cancer Res. 2012;72:1865–77.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Lu YC, Chen YJ, Wang HM, Tsai CY, Chen WH, Huang YC, et al. Oncogenic function and early detection potential of miRNA-10b in oral cancer as identified by microRNA profiling. Cancer Prev Res (Phila). 2012;5:665–74.CrossRefGoogle Scholar
  52. 52.
    Garzon R, Pichiorri F, Palumbo T, Visentini M, Aqeilan R, Cimmino A, et al. MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia. Oncogene. 2007;26:4148–57.CrossRefPubMedGoogle Scholar
  53. 53.
    Zhang Y, Li M, Wang H, Fisher WE, Lin PH, Yao Q, et al. Profiling of 95 microRNAs in pancreatic cancer cell lines and surgical specimens by real-time pcr analysis. World J Surg. 2009;33:698–709.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Mairinger FD, Ting S, Werner R, Walter RF, Hager T, Vollbrecht C, et al. Different micro-RNA expression profiles distinguish subtypes of neuroendocrine tumors of the lung: Results of a profiling study. Mod Pathol. 2014;27:1632–40.CrossRefPubMedGoogle Scholar
  55. 55.
    Sun L, Yao Y, Liu B, Lin Z, Lin L, Yang M, et al. Mir-200b and mir-15b regulate chemotherapy-induced epithelial-mesenchymal transition in human tongue cancer cells by targeting bmi1. Oncogene. 2012;31:432–45.CrossRefPubMedGoogle Scholar
  56. 56.
    Wu CS, Yen CJ, Chou RH, Chen JN, Huang WC, Wu CY, et al. Downregulation of microRNA-15b by hepatitis b virus x enhances hepatocellular carcinoma proliferation via fucosyltransferase 2-induced globo h expression. Int J Cancer. 2014;134:1638–47.CrossRefPubMedGoogle Scholar
  57. 57.
    Kim S, Kang H. Mir-15b induced by platelet-derived growth factor signaling is required for vascular smooth muscle cell proliferation. BMB Rep. 2013;46:550–4.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Zhao Z, Zhang L, Yao Q, Tao Z. Mir-15b regulates cisplatin resistance and metastasis by targeting pebp4 in human lung adenocarcinoma cells. Cancer Gene Ther. 2015;22:108–14.CrossRefPubMedGoogle Scholar
  59. 59.
    Weirauch U, Beckmann N, Thomas M, Grünweller A, Huber K, Bracher F, et al. Functional role and therapeutic potential of the pim-1 kinase in colon carcinoma. Neoplasia. 2013;15:783–IN728.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Loayza-Puch F, Yoshida Y, Matsuzaki T, Takahashi C, Kitayama H, Noda M. Hypoxia and ras-signaling pathways converge on, and cooperatively downregulate, the reck tumor-suppressor protein through microRNAs. Oncogene. 2010;29:2638–48.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Ci Zhao
    • 1
  • Guanyu Wang
    • 1
  • Yuanyuan Zhu
    • 1
  • Xiaobo Li
    • 2
  • Feihu Yan
    • 1
  • Chunhui Zhang
    • 1
  • Xiaoyi Huang
    • 3
  • Yanqiao Zhang
    • 1
  1. 1.Department of Gastrointestinal Medical OncologyThe Affiliated Tumour Hospital of Harbin Medical UniversityHarbinChina
  2. 2.Department of PathologyHarbin Medical UniversityHarbinChina
  3. 3.Department of BiotherapyThe Affiliated Tumour Hospital of Harbin Medical UniversityHarbinChina

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