journal contribution
posted on 2023-03-31, 01:25 authored by Yimeng Zhang, Ting Wang, Shan Wang, Yanlu Xiong, Rui Zhang, Xiang Zhang, Jing Zhao, An-Gang Yang, Lei Wang, Lintao Jia This file contains supplementary figures showing the survival times of medulloblastoma (MB) model mice used throughout the present study (Fig. S1), a heatmap of differentially expressed genes between CGNPs and MB cells (Fig. S2), the capability of Nkx2-2as to suppress the stem-like properties of MB cells (Fig. S3), bioinformatics prediction of miRNAs potentially bound to Nkx2-2as (Fig. S4) and the candidate targets of these miRNAs (Fig. S5), a ChIP proof for the inability of Gli2 to occupy the Nkx2-2as promoter (Fig. S6), and finally the typical GAB1 staining results to distinguish Shh subtype clinical MBs (Fig. S7).
Funding
National Natural Science Foundation of China
History
ARTICLE 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.
