Prognostic and microRNA profile analysis for CD44 positive expression pediatric posterior fossa ependymoma
- 191 Downloads
Ependymoma is the third most common pediatric brain tumor and occurs most frequently in the posterior fossa. However, the lack of immortalized cell lines, xenografts, or animal models has significantly hindered the study of pediatric posterior fossa ependymoma (P-PF-EPN) pathogenesis. This prompted us to use clinical big data to study this rare disease.
Application of the robust rank aggregation method revealed CD44 as a reliable biomarker in P-PF-EPN. 120 P-PF-EPN samples after surgical resection were selected for Kaplan–Merier and Cox proportion hazard regression survival analysis. Immunohistochemical analysis was performed to assess CD44 expression in the tumor samples. The miRNA profile was determined using a whole-genome miRNA microarray. The expression patterns of related mRNAs, miRNAs and proteins were validated by qRT-PCR or Western blotting.
CD44 was found to be an independent predictor of prognosis in survival analysis. It improved the accuracy of using LAMA2/NELL2 for classifying P-PF-EPN molecular subgroups. Fourteen miRNAs were underexpressed, and one miRNA was overexpressed in CD44-positive P-PF-EPNs. miR-543, miR-495-3p, miR-299-3p, miR-139-5p and miR-128-3p were identified to have CD44 positively co-regulated potential target oncogenes. Two PI3K-Akt signaling pathway related potential target oncogenes (VEGFA, CSF1) for miR-299-3p and miR-495-3p were validated overexpression in CD44 positive P-PF-EPNs. Abnormal activation of the PI3K-Akt pathway was confirmed in CD44-positive cases.
CD44 is of great clinical significance as a prognostic biomarker. The survival difference between CD44 positive and negative P-PF-EPN is determined by a complex functional miRNA-mRNA-signaling pathway regulatory network.
KeywordsPediatric ependymoma CD44 Survival miRNA Prognostic biomarker
Thanks are due to the School of Medicine Nankai University for the assistance with the experiments.
The study was supported by the Foundation of Tianjin Science and Technology Committee (14JCZDJC35600) and the National Key Technology Support Program (2014BAI04B00).
Compliance with ethical standards
Conflict of interest
The authors declare that no conflicts of interest exist with regard to this manuscript.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 1.de Bont JM, den Boer ML, Kros JM, Passier MM, Reddingius RE, Smitt PA, et al. Identification of novel biomarkers in pediatric primitive neuroectodermal tumors and ependymomas by proteome-wide analysis. J Neuropathol Exp Neurol. 2007;66(6):505–16. https://doi.org/10.1097/01.jnen.0000240475.35414.c3.CrossRefPubMedGoogle Scholar
- 6.Tihan T, Zhou T, Holmes E, Burger PC, Ozuysal S, Rushing EJ. The prognostic value of histological grading of posterior fossa ependymomas in children: a Children’s Oncology Group study and a review of prognostic factors. Mod Pathol. 2008;21(2):165–77. https://doi.org/10.1038/modpathol.3800999.CrossRefPubMedGoogle Scholar
- 7.Ellison DW, Kocak M, Figarella-Branger D, Felice G, Catherine G, Pietsch T, et al. Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts. J Negat Results Biomed. 2011;10:7. https://doi.org/10.1186/1477-5751-10-7.CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Rogers HA, Mayne C, Chapman RJ, Kilday JP, Coyle B, Grundy RG. PI3K pathway activation provides a novel therapeutic target for pediatric ependymoma and is an independent marker of progression-free survival. Clin Cancer Res. 2013;19(23):6450–60. https://doi.org/10.1158/1078-0432.CCR-13-0222.CrossRefPubMedGoogle Scholar
- 18.Pajtler KW, Witt H, Sill M, Jones DT, Hovestadt V, Kratochwil F, et al. Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell. 2015;27(5):728–43. https://doi.org/10.1016/j.ccell.2015.04.002.CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Ramaswamy V, Hielscher T, Mack SC, Lassaletta A, Lin T, Pajtler KW, et al. Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis. J Clin Oncol. 2016;34(21):2468–77. https://doi.org/10.1200/JCO.2015.65.7825.CrossRefPubMedPubMedCentralGoogle Scholar