Title | Downregulation of CRX, a Group 3-specific oncogenic transcription factor, inhibits TGF-β activin signaling in medulloblastoma cells [Genomics Facility] |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Masurkar SArun, Deogharkar A, Bharambe HShrikrishn, Shirsat NVishwanath |
Journal | Biochemical and Biophysical Research Communications |
Volume | 568 |
Start Page | 76 |
Pagination | 76–82 |
Date Published | 06/2021 |
Type of Article | Journal Article |
ISSN | 0006-291X |
Keywords | CRX, Group 3, Medulloblastoma, TGF-β/activin signaling |
Abstract | Medulloblastoma, the most common malignant brain tumor in children, consists of four molecular subgroups WNT, SHH, Group 3, and Group 4. Group 3 has the worst survival rate among the four subgroups and is characterized by the expression of retina-specific genes. CRX, the master regulator of the photoreceptor differentiation, is aberrantly expressed in Group 3 medulloblastomas. CRX expression increased the proliferation, anchorage-independent growth, invasion potential, and tumorigenicity of medulloblastoma cells indicating the oncogenic role of CRX in medulloblastoma pathogenesis. CRX knockdown resulted in the downregulation of expression of several retina-specific genes like IMPG2, PDC, RCVRN. and Group 3 specific genes like GABRA5, MYC, PROM1. Thus, CRX plays a major role not only in the expression of retina-specific genes but also in defining Group 3 identity. Increased expression of several pro-apoptotic genes upon CRX knockdown suggests that CRX could protect Group 3 medulloblastoma cells from cell death. Several negative regulators of the TGF-β signaling pathway like SMAD7, PMEPA1, KLF2 were upregulated upon the CRX knockdown. Western blot analysis showed a decrease in the levels of (Phospho)-SMAD2, total levels of SMAD2, SMAD4, and an increase in the levels of SMAD7 indicating inhibition of the TGF-β signaling pathway upon CRX knockdown. Copy number variations in several genes involved in the TGF-β signaling pathway occur in a subset of Group 3 tumors. Autocrine TGF-β/activin signaling has recently been reported to be active in a subset of Group 3 medulloblastomas. CRX knockdown resulting in the inhibition of the TGF-β/activin signaling pathway demonstrates an interaction between the two Group 3 specific oncogenic pathways and suggests simultaneous targeting of both CRX and TGF-β signaling as a possible therapeutic strategy. |
URL | https://www.sciencedirect.com/science/article/abs/pii/S0006291X21009888 |
DOI | 10.1016/j.bbrc.2021.06.064 |
PubMed ID | 34192607 |
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