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Biochem Biophys Res Commun ; 568: 76-82, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34192607

RESUMO

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-ß 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-ß signaling pathway upon CRX knockdown. Copy number variations in several genes involved in the TGF-ß signaling pathway occur in a subset of Group 3 tumors. Autocrine TGF-ß/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-ß/activin signaling pathway demonstrates an interaction between the two Group 3 specific oncogenic pathways and suggests simultaneous targeting of both CRX and TGF-ß signaling as a possible therapeutic strategy.


Assuntos
Ativinas/metabolismo , Neoplasias Cerebelares/genética , Proteínas de Homeodomínio/genética , Meduloblastoma/genética , Transdução de Sinais , Transativadores/genética , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem Celular Tumoral , Neoplasias Cerebelares/metabolismo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , Meduloblastoma/metabolismo , Camundongos Endogâmicos NOD , Camundongos SCID
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