ZEB1 EXPRESSION IN MEDULLOBLASTOMA: IN SILICO ANALYSIS

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  • Presentation type: DR - Doctoral Student
  • Track: 1. Bioinformatics
  • Keywords: ZEB1; Medulloblastoma; EMT; metastasis;

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  • 1 Universidade Federal do Rio Grande do Sul

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Abstract

INTRODUCTION AND OBJECTIVES: Medulloblastoma (MB) arises in the cerebellum and is the most common malignant Central Nervous System tumor in pediatric patients. The prognosis for patients diagnosed with this neoplasia varies among molecular subgroups, with worse outcomes in Group 3 and Group 4. The transcription factor ZEB1 induces epithelial-to-mesenchymal transition and participates in the cerebellum formation. In addition, it is linked to worse prognosis in several solid cancers, regulating gene and microRNA (miR) expression. We aim to investigate ZEB1 expression and clinical impact in MB, using an in silico approach. MATERIAL AND METHODS: GSE85217 (n=753) and GSE28192 (n=92) microarray data were acquired from R2 platform and analyzed using “survminer”, “survival” and “RTCGA” packages on R (version 4.0.4). RESULTS AND CONCLUSION: ZEB1 expression is higher in normal cerebellar tissue (n=12) when compared to MB samples (n=18) (Wilcoxon test, p=0.00024), corroborating the in vivo data reported by Singh et al (2016), where ZEB1 expression was increased MB in comparison to postnatal mice. Among molecular MB subgroups, the SHH subgroup shows increased levels of ZEB1; no difference to controls was found in the other subgroups (Kruskall-Wallis followed by Dunn’s test, p<0.001). Based on ZEB1 expression, a cutoff was calculated to each molecular subgroup, defining two populations with low and high ZEB1. In Group 3 and Group 4, patients with increased ZEB1 expression presented poorer outcomes. In the WNT subgroup, which presents the most favorable MB prognosis, high ZEB1 levels were reported in patients with better outcomes. The higher ZEB1 expression levels found in SHH contrast with no statistical significance in survival analysis. Surprisingly, ZEB1 expression was decreased in patients which presented metastasis (Wilcoxon test, p < 0.05). This unexpected result was conducted in samples from primary sites and maybe an analysis of ZEB1 expression in samples from metastatic sites would help understanding ZEB1 role in MB metastasis. Taken together, these results support ZEB1 clinical relevance in MB and may suggest researching ZEB1 as a potential target.

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Author

Lívia DUTRA

Boa tarde, Denise! Excelente pergunta! A análise de E-caderina, N-cadherina e Vimentina foi feita no total de amostras e em amostras positivas para metástase, entretanto, nenhuma relação foi observada. A expressão desses três marcadores entretanto, não foi analisada ainda de acordo com o subgrupo molecular. Muito grata pela observação!

Author

Lívia DUTRA

Olá Anderson, obrigada pela pergunta!

ZEB1 é downstream/participa de importantes vias como TGF-Beta, NF-kB, PI3K/Akt e Ras/ERK. O trabalho agora vai investigar a relação de ZEB1 com alguns microRNAs selecionados in silico, a expressão de alvos e a sua modulação por agentes epigenéticos. 

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Author

Lívia DUTRA

Bom dia, André! Sim, a expressão de ZEB1 é diferente entre os subgrupos moleculares de meduloblastoma: mais alta em SHH do que nos demais, que não demonstram diferença entre si. ZEB1 é necessário para o correto desenvolvimento do cerebelo e está relacionado ao subgrupo SHH (Singh et al., 2016). Relação de causalidade com outros subgrupos ainda não foi investigada. Apesar de estar mais expresso em SHH, só encontramos associação de ZEB1 com sobrevida nos grupos moleculares 3 e 4. Em WNT, o grupo com melhor prognóstico clínico, encontramos uma associação diferente com a sobrevida: maior expressão de ZEB1 em pacientes com melhor prognóstico. Em SHH, nenhuma associação com sobrevida foi encontrada. Talvez tenha ficado confuso na apresentação, mas nós esperávamos que ele fosse mais expresso em pacientes que apresentavam metástase, e não o contrário, como foi observado. 

Obrigada pelos questionamentos!