Centro de Investigação em Biociências e Tecnologias da Saúde

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Impact of the human Golgi anti-apoptotic protein (hGAAP/TMBIM4) in Glioblastoma progression

Publication . Martins, Marta Filipa Malheiro; Saraiva, Nuno Ricardo de Almeida; Gomes, Edgar Rodrigues Almeida

The progression and severity of gliomas are strongly associated with their ability to spread and invade other tissues. Along with drug targeting constraints, the high level of heterogeneity hampers the development of broad therapeutic strategies. Several members of the Transmembrane BAX Inhibitor Motif-containing (TMBIM) family of transmembrane proteins can modulate various cellular processes central to cancer progression. These include apoptosis resistance, promotion of cell motility, extracellular matrix (ECM) remodelling, and changes in the cellular metabolic status. This works aims at exploring the impact of members of this family of proteins on glioma progression. Gene expression (mRNA) and patient survival bioinformatics analysis was performed, using the TCGA (The Cancer Genome Atlas), CGGA (Chinese Glioma Genome Atlas), and Ivy GAP (Ivy Glioblastoma Atlas Project) databases. Four glioblastoma multiforme (GBM) cells lines (8-MG, U- 87MG, U251 e GL15) were used as models. To explore the mechanisms underlying the effects of TMBIM4 upregulation of TMBIM4 in glioma progression, cells were transfected with TMBIM4-specific siRNAs. Two- and three-dimensional cell invasion were assessed by ECM-coated transwell and ECM-embedded spheroid assays, respectively. Gene expression analysis indicated that the level of most TMBIMs mRNAs is dysregulated in gliomas. Particularly, TMBIM1, 4 and 6 are upregulated in GBM when compared with normal tissues. The increased expression of TMBIM1, 4 and 6 positively is associated with glioma grade. All three genes are overexpressed in the mesenchymal and neural GBM subtypes. Laser-dissected GBM tissue analysis (Ivy GAP) confirmed the increased levels of TMBIM1 and 4 in the cellular tumour vs tumour edge. Importantly, high levels of TMBIM1 and 4 are associated with a significant reduction in the survival of low-grade glioma patients but not of GBM patients. These data suggest a possible role for TMBIM1 and 4 in glioma progression. The downregulation of TMBIM4 provoked a strong inhibition of 2D cell invasion in three GBM cell lines tested (U-87MG, U251, GL 15), without affecting cell viability. TMBIM4 knock-down also leads to a robust reduction of 3D cell invasion in U87 cells. U87 cells with reduced TMBIM4 expression have a smaller size and an increased number of cell protrusions when compared with control cells. Ongoing studies aim at evaluating the effect of TMBIM4 expression in glioma in vivo invasion and at dissecting the molecular mechanisms involved. Here, data is presented that support further exploration of TMBIM1 and TMBIM4 as potential novel markers for glioma progression. Thus, contributing to the refinement of glioma diagnosis and possibly to the development of new therapeutic strategies

2021-06-15Dissertação de mestrado

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Entidade financiadora

Fundação para a Ciência e a Tecnologia

Programa de financiamento

6817 - DCRRNI ID

Número da atribuição

UID/DTP/04567/2019