Distinctive microRNA signature of medulloblastomas associated with the WNT signaling pathway
Amit Gokhale1, Ratika Kunder1, Atul Goel2, Rajiv Sarin1, Aliasgar Moiyadi1, Asha Shenoy3, Chandrasekhar Mamidipally4, Santosh Noronha4, Sadhana Kannan1, Neelam Vishwanath Shirsat1
1 Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India
2 Department of Neurosurgery, Seth G. S. Medical College and K.E.M. Hospital, Parel, Mumbai 400012, Maharashtra, India
3 Department of Pathology, Seth G. S. Medical College and K.E.M. Hospital, Parel, Mumbai 400012, Maharashtra, India
4 Department of Chemical Engineering, School of Bioscience and Bioengineering, Systems and Control, Indian Institute of Technology, Mumbai 400076, Maharashtra, India
Neelam Vishwanath Shirsat
Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra
Source of Support: Indian Council of Medical Research, India; The Terry Fox Foundation, Canada; Fellowship from the Council of Scientific and Industrial Research, India.,, Conflict of Interest: None
Aim: Medulloblastoma is a malignant brain tumor that occurs predominantly in children. Current risk stratification based on clinical parameters is inadequate for accurate prognostication. MicroRNA expression is known to be deregulated in various cancers and has been found to be useful in predicting tumor behavior. In order to get a better understanding of medulloblastoma biology, miRNA profiling of medulloblastomas was carried out in parallel with expression profiling of protein-coding genes.
Materials and Methods: miRNA profiling of medulloblastomas was carried out using Taqman Low Density Array v 1.0 having 365 human microRNAs. In parallel, genome-wide expression profiling of protein-coding genes was carried out using Affymetrix gene 1.0 ST arrays.
Results: Both the profiling studies identified four molecular subtypes of medulloblastomas. Expression levels of select protein-coding genes and miRNAs could classify an independent set of medulloblastomas. Twelve of 31 medulloblastomas were found to overexpress genes belonging to the canonical WNT signaling pathway and carry a mutation in CTNNB1 gene. A number of miRNAs like miR-193a, miR-224/miR-452 cluster, miR-182/miR-183/miR-96 cluster, and miR-148a having potential tumor/metastasis suppressive activity were found to be overexpressed in the WNT signaling associated medulloblastomas. Exogenous expression of miR-193a and miR-224, two miRNAs that have the highest WNT pathway specific upregulation, was found to inhibit proliferation, increase radiation sensitivity and reduce anchorage-independent growth of medulloblastoma cells.
Conclusion: Expression level of tumor/metastasis suppressive miRNAs in the WNT signaling associated medulloblastomas is likely to determine their response to treatment, and thus, these miRNAs would be important biomarkers for risk stratification within the WNT signaling associated medulloblastomas.