Skip to main content

Advertisement

SpringerLink
Log in

Mir-449a, a potential diagnostic biomarker for WNT group of medulloblastoma

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in childhood. The 5 year disease-free survival rate is rather low. There is a consensus that MB can be divided into at least four clinically, transcriptionally, and genetically distinct molecular variants, being designated as wingless (WNT), sonic hedgehog (SHH), Group 3 and Group 4. It poses a great challenge to the design of therapeutic strategy for MB patients. Intensive clinical intervention, including high dose radiotherapy, is commonly used in treatment of high risk MB, most of which are considered to be Group 3 patients. But such intensive therapy should be avoided to protect neurologic function of patients in the lower risk WNT group. In present study, MB subgroup assignment in formalin-fixed paraffin embedded (FFPE) specimens from 45 Chinese patients were performed by Nanostring platform using 22 well-known signature genes. Based on comparative expression profiles of miRNA real-time PCR microarray in MB cells with and without treatment of demethylation reagent, as well as MSP assay, miR-449a was demonstrated to be significantly silenced by aberrant DNA methylation in tumor cells. Real-time PCR showed that expression level of miR-449a in WNT group was significantly different from other subgroups, although it was down-regulated in most of the MB samples. In conclusion, current study demonstrates for the first time the feasibility of using the Nanostring assay for subgrouping of MBs in Chinese patients. In addition, MiR-449a, a candidate tumor suppressor regulated by hypermethylation, is a novel potential diagnostic marker for WNT group of MBs.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Gajjar A, Chintagumpala M, Ashley D, Kellie S, Kun LE, Merchant TE et al (2006) Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol 7:813–820

    Article  PubMed  Google Scholar 

  2. Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL et al (2006) Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 24:4202–4208

    Article  CAS  PubMed  Google Scholar 

  3. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol (Berl) 114:97–109

    Article  Google Scholar 

  4. Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S et al (2011) Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29:1408–1414

    Article  PubMed  Google Scholar 

  5. Northcott PA, Shih DJ, Remke M, Cho YJ, Kool M, Hawkins C et al (2012) Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples. Acta Neuropathol (Berl) 123:615–626

    Article  CAS  Google Scholar 

  6. Beard RE, Abate-Daga D, Rosati SF, Zheng Z, Wunderlich JR, Rosenberg SA et al (2013) Gene expression profiling using nanostring digital RNA counting to identify potential target antigens for melanoma immunotherapy. Clin Cancer Res 19:4941–4950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kim VN (2005) MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol 6:376–385

    Article  CAS  PubMed  Google Scholar 

  8. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E et al (2002) Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 99:15524–15529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Garzon R, Fabbri M, Cimmino A, Calin GA, Croce CM (2006) MicroRNA expression and function in cancer. Trends Mol Med 12:580–587

    Article  CAS  PubMed  Google Scholar 

  11. Sarkar S, Dubaybo H, Ali S, Goncalves P, Kollepara SL, Sethi S et al (2013) Down-regulation of miR-221 inhibits proliferation of pancreatic cancer cells through up-regulation of PTEN, p27(kip1), p57(kip2), and PUMA. Am J Cancer Res 3:465–477

    PubMed  PubMed Central  Google Scholar 

  12. Li H, Yu G, Shi R, Lang B, Chen X, Xia D et al (2014) Cisplatin-induced epigenetic activation of miR-34a sensitizes bladder cancer cells to chemotherapy. Mol Cancer 13:8

    Article  PubMed  PubMed Central  Google Scholar 

  13. Du L, Zhao Z, Ma X, Hsiao TH, Chen Y, Young E et al (2014) miR-93-directed downregulation of DAB2 defines a novel oncogenic pathway in lung cancer. Oncogene 33:4307–4315

    Article  CAS  PubMed  Google Scholar 

  14. Zhao Z, Ma X, Sung D, Li M, Kosti A, Lin G et al (2015) microRNA-449a functions as a tumor suppressor in neuroblastoma through inducing cell differentiation and cell cycle arrest. RNA Biol 12:538–554

    Article  PubMed  PubMed Central  Google Scholar 

  15. Genovesi LA, Carter KW, Gottardo NG, Giles KM, Dallas PB (2011) Integrated analysis of miRNA and mRNA expression in childhood medulloblastoma compared with neural stem cells. PloS One 6:e23935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Venkataraman S, Birks DK, Balakrishnan I, Alimova I, Harris PS, Patel PR et al (2013) MicroRNA 218 acts as a tumor suppressor by targeting multiple cancer phenotype-associated genes in medulloblastoma. J Biol Chem 288:1918–1928

    Article  CAS  PubMed  Google Scholar 

  17. Ferretti E, De Smaele E, Po A, Di Marcotullio L, Tosi E, Espinola MS et al (2009) MicroRNA profiling in human medulloblastoma. Int J Cancer 124:568–577

    Article  CAS  PubMed  Google Scholar 

  18. Miska EA (2005) How microRNAs control cell division, differentiation and death. Current Opin Genet Dev 15:563–568

    Article  CAS  Google Scholar 

  19. Yang F, Bi J, Xue X, Zheng L, Zhi K, Hua J et al (2012) Up-regulated long non-coding RNA H19 contributes to proliferation of gastric cancer cells. FEBS J 279:3159–3165

    Article  CAS  PubMed  Google Scholar 

  20. Pierson J, Hostager B, Fan R, Vibhakar R (2008) Regulation of cyclin dependent kinase 6 by microRNA 124 in medulloblastoma. J Neurooncol 90:1–7

    Article  CAS  PubMed  Google Scholar 

  21. Shalaby T, Fiaschetti G, Baumgartner M, Grotzer MA (2014) MicroRNA signatures as biomarkers and therapeutic target for CNS embryonal tumors: the pros and the cons. Int J Mol Sci 15:21554–21586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Northcott PA, Fernandez LA, Hagan JP, Ellison DW, Grajkowska W, Gillespie Y et al (2009) The miR-17/92 polycistron is up-regulated in sonic hedgehog-driven medulloblastomas and induced by N-myc in sonic hedgehog-treated cerebellar neural precursors. Cancer Res 69:3249–3255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Weeraratne SD, Amani V, Teider N, Pierre-Francois J, Winter D, Kye MJ et al (2012) Pleiotropic effects of miR-183 ~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma. Acta Neuropathol (Berl) 123:539–552

    Article  CAS  Google Scholar 

  24. Chang Q, Pang JC, Li KK, Poon WS, Zhou L, Ng HK (2005) Promoter hypermethylation profile of RASSF1A, FHIT, and sFRP1 in intracranial primitive neuroectodermal tumors. Hum Pathol 36:1265–1272

    Article  CAS  PubMed  Google Scholar 

  25. Pang JC, Chang Q, Chung YF, Teo JG, Poon WS, Zhou LF et al (2005) Epigenetic inactivation of DLC-1 in supratentorial primitive neuroectodermal tumor. Hum Pathol 36:36–43

    Article  CAS  PubMed  Google Scholar 

  26. Shao LW, Pan Y, Qi XL, Li YX, Ma XL, Yi WN et al (2016) ATRX loss in adult supratentorial diffuse astrocytomas correlates with p53 over expression and IDH1 mutation and predicts better outcome in p53 accumulated patients. Histol Histopathol 31:103–114

    PubMed  Google Scholar 

  27. Zhou X, Zhu W, Li H, Wen W, Cheng W, Wang F et al (2015) Diagnostic value of a plasma microRNA signature in gastric cancer: a microRNA expression analysis. Sci Rep 5:11251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yao Y, Ma J, Xue Y, Wang P, Li Z, Li Z et al (2015) MiR-449a exerts tumor-suppressive functions in human glioblastoma by targeting Myc-associated zinc-finger protein. Mol Oncol 9:640–656

    Article  CAS  PubMed  Google Scholar 

  29. Yang X, Feng M, Jiang X, Wu Z, Li Z, Aau M et al (2009) miR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate pRb-E2F1 activity through a feedback loop by targeting CDK6 and CDC25A. Genes Dev 23:2388–2393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chen J, Zhou J, Chen X, Yang B, Wang D, Yang P et al (2015) miRNA-449a is downregulated in osteosarcoma and promotes cell apoptosis by targeting BCL2. Tumour Biol 36:8221–8229

    Article  CAS  PubMed  Google Scholar 

  31. Yuan JM, Shi XJ, Sun P, Liu JX, Wang W, Li M et al (2015) Downregulation of cell cycle-related proteins in ovarian cancer line and cell cycle arrest induced by microRNA. Int J Clin Exp Med 8:18476–18481

    PubMed  PubMed Central  Google Scholar 

  32. Chen SP, Liu BX, Xu J, Pei XF, Liao YJ, Yuan F et al (2015) MiR-449a suppresses the epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma by multiple targets. BMC Cancer 15:706

    Article  PubMed  PubMed Central  Google Scholar 

  33. Shi W, Bruce J, Lee M, Yue S, Rowe M, Pintilie M et al (2016) MiR-449a promotes breast cancer progression by targeting CRIP2. Oncotarget.doi:10.18632/oncotarget.7753

    Google Scholar 

  34. Chen S, Dai Y, Zhang X, Jin D, Li X, Zhang Y (2014) Increased miR-449a expression in colorectal carcinoma tissues is inversely correlated with serum carcinoembryonic antigen. Oncol Lett 7:568–572

    PubMed  Google Scholar 

  35. You J, Zhang Y, Li Y, Fang N, Liu B, Zu L et al (2015) MiR-449a suppresses cell invasion by inhibiting MAP2K1 in non-small cell lung cancer. Am J Cancer Res 5:2730–2744

    PubMed  PubMed Central  Google Scholar 

  36. Reis PP, Waldron L, Goswami RS, Xu W, Xuan Y, Perez-Ordonez B et al (2011) mRNA transcript quantification in archival samples using multiplexed, color-coded probes. BMC Biotechnol 11:46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Geiss GK, Bumgarner RE, Birditt B, Dahl T, Dowidar N, Dunaway DL et al (2008) Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat Biotechnol 26:317–325

    Article  CAS  PubMed  Google Scholar 

  38. Cho YJ, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H et al (2011) Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol 29:1424–1430

    Article  PubMed  Google Scholar 

  39. Kool M, Koster J, Bunt J, Hasselt NE, Lakeman A, van Sluis P et al (2008) Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PloS One 3:e3088

    Article  PubMed  PubMed Central  Google Scholar 

  40. Gupta T, Shirsat N, Jalali R (2015) Molecular subgrouping of medulloblastoma: impact upon research and clinical practice. Curr Pediatr Rev 11:106–119

    Article  CAS  PubMed  Google Scholar 

  41. Gokhale A, Kunder R, Goel A, Sarin R, Moiyadi A, Shenoy A et al (2010) Distinctive microRNA signature of medulloblastomas associated with the WNT signaling pathway. J Cancer Res Ther 6:521–529

    Article  CAS  PubMed  Google Scholar 

  42. Iliopoulos D, Bimpaki EI, Nesterova M, Stratakis CA (2009) MicroRNA signature of primary pigmented nodular adrenocortical disease: clinical correlations and regulation of Wnt signaling. Cancer Res 69:3278–3282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Curran EK, Sainani KL, Le GM, Propp JM, Fisher PG (2009) Gender affects survival for medulloblastoma only in older children and adults: a study from the surveillance epidemiology and end results registry. Pediatr Blood Cancer 52:60–64

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No. 81101900) and the Clinicopathologic Innovation Fund from Peking University Third Hospital, Peking University Health Science Center to Qing Chang, MD., Ph.D.

Author information

Authors and Affiliations

  1. Department of Pathology, Peking University School of Basic Medical Science, Peking University Third Hospital, Peking Univeristy Health Science Center, Xue Yuan Road 38#, Beijing, 100191, China

    Yongxiao Li, Liwei Shao, Yan Liu, Chen Zheng, Yanfeng Zhong, Jing Zhang & Qing Chang

  2. Department of Neurosurgery, Beijing Tiantan Hospital, Beijing, China

    Tao Jiang

  3. Department of Neuropathology, University of Washington, Seattle, WA, USA

    Jing Zhang

Authors
  1. Yongxiao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tao Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liwei Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chen Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yanfeng Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qing Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qing Chang.

Ethics declarations

Conflict of interest

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Jiang, T., Shao, L. et al. Mir-449a, a potential diagnostic biomarker for WNT group of medulloblastoma. J Neurooncol 129, 423–431 (2016). https://doi.org/10.1007/s11060-016-2213-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-016-2213-y

Keywords

Search

Navigation