Abstract
Medulloblastoma, a common pediatric malignant brain tumor consists of four molecular subgroups viz. WNT, SHH, Group 3 and Group 4. MiR-148a is over-expressed in the WNT subgroup tumors, which have the lowest incidence of metastasis and excellent survival among all medulloblastomas. MiR-148a was expressed either in a transient manner using a synthetic mimic or in a stable doxycycline inducible manner using a lentiviral vector in non-WNT medulloblastoma cell lines. Expression of miR-148a to levels comparable to that in the WNT subgroup tumors was found to inhibit proliferation, clonogenic potential, invasion potential and tumorigenicity of medulloblastoma cells. MiR-148a expression in medulloblastoma cells brought about reduction in the expression of NRP1, a novel miR-148a target. Restoration of NRP1 expression in medulloblastoma cells was found to rescue the reduction in the invasion potential and tumorigenicity brought about by miR-148a expression. NRP1 is known to play role in multiple signaling pathways that promote tumor growth, invasion and metastasis. NRP1 expression in medulloblastomas was found to be associated with poor survival, with little or no expression in majority of the WNT tumors. The tumor suppressive effect of miR-148a expression accompanied by the down-regulation of NRP1 makes miR-148a an attractive therapeutic agent for the treatment of medulloblastomas.
Highlights
Brain tumors are the most common solid tumors in children
MiR-148a expression was studied in a total of 141 medulloblastoma tumor tissues by real time Reverse TranscriptionPolymerase Chain Reaction (RT-Polymerase Chain reaction (PCR)) analysis
WNT subgroup medulloblastomas were found to over express miR-148a by 6-12 fold (p < 0.0001) as compared to www.impactjournals.com/oncoscience the other subgroup tumors, 10-20 fold as compared to normal cerebellar tissues and 7-100 fold as compared to the established medulloblastoma cell lines (Figure 1A)
Summary
Brain tumors are the most common solid tumors in children. Medulloblastomas account for about 20% of all primary brain tumors in children. Genome wide expression profiling www.impactjournals.com/oncoscience studies have identified four core molecular subgroups of medulloblastomas called WNT, SHH, Group 3 and Group 4 [2]. MYC over-expression/amplification and expression of the photoreceptor signaling pathway genes is a characteristic of most Group 3 tumors while Group 4 tumors are characterized by the expression of various neuronal differentiation related genes [2, 4]. The four molecular subgroups vary in clinical characteristics like age related incidence, presence of metastasis and survival. Group 3 tumors have the highest incidence of metastasis at diagnosis and poor overall survival. WNT subgroup medulloblastomas on the other hand have the lowest incidence of metastasis at diagnosis (< 10%) and highest survival (90% - 95% ten year overall survival) among all the four subgroups [5]
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