Abstract
Aberrant Hedgehog signaling and excessive activation of the Gli family of transcriptional activators are key drivers of medulloblastoma (MB), the most common human pediatric brain malignancy. MB originates mainly from cerebellar granule neuron progenitors (CGNP), but the mechanisms underlying CGNP transformation remain largely obscure. In this study, we found that suppression of the noncoding RNA Nkx2-2as promoted Sonic Hedgehog (Shh)-potentiated MB development. Nkx2-2as functioned as a competing endogenous RNA against miR-103 and miR-107, sequestering them and thereby derepressing their tumor suppressive targets BTG2 and LATS1 and impeding cell division and migration. We also found that Nkx2-2as tethered miR-548m and abrogated its LATS2 targeting activity. Shh signaling impaired Nkx2-2as expression by upregulating the transcriptional repressor FoxD1. In clinical specimens of Shh-subgroup MB, we validated coordinated expression of the aforementioned proteins. Notably, exogenous expression of Nkx2-2as suppressed tumorigenesis and prolonged animal survival in MB mouse models. Our findings illuminate the role of noncoding RNAs in Hedgehog signaling and MB occurrence, with implications for identifying candidate therapeutic targets for MB treatment.Significance: These findings illuminate the role of noncoding RNAs in Hedgehog signaling and an interplay between the Hedgehog and Hippo pathways in medulloblastoma pathogenesis. Cancer Res; 78(4); 962-73. ©2017 AACR.
Highlights
Medulloblastoma (MB) is the most common type of pediatric brain malignancy [1]
The Long noncoding RNAs (lncRNA) Nkx2-2as is downregulated in Sonic Hedgehog (Shh)-driven MB cells To explore the genes involved in tumorigenesis, we utilized a spontaneous orthotopic MB model driven by Hedgehog signaling
Despite the established role of Gli transcription factors in canonical Shh signaling, the downstream molecular mechanisms that account for the development of Shh-type MBs remain to be elucidated [7]
Summary
Medulloblastoma (MB) is the most common type of pediatric brain malignancy [1]. Due to the limited prognostic value of previous histological groupings, molecular typing of clinical MBs is necessary [3, 4]. Along these lines, a recent integrated genomic profiling study revealed that MB consists of at least four distinct molecular subgroups with significant differences in their demographic, genetic, and symptomatic features: Wnt, Sonic Hedgehog (Shh), group 3, and group 4 [1, 3]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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