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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Loss of 5 `-Methylthioadenosine Phosphorylase (MTAP) is Frequent in High-Grade Gliomas; Nevertheless, it is Not Associated with Higher Tumor Aggressiveness

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Autor(es):
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de Menezes, Weder Pereira [1] ; Oliveira Silva, Viviane Aline [1] ; Faria Gomes, Izabela Natalia [1] ; Rosa, Marcela Nunes [1] ; Corcoll Spina, Maria Luisa [1] ; Carloni, Adriana Cruvinel [1] ; Vieira Alves, Ana Laura [1] ; Melendez, Matias [1] ; Almeida, Gisele Caravina [2] ; da Silva, Luciane Sussuchi [1] ; Clara, Carlos [3] ; da Cunha, Isabela Werneck [4] ; Maroso Hajj, Glaucia Noeli [4] ; Jones, Chris [5] ; Bidinotto, Lucas Tadeu [1, 6, 7] ; Reis, Rui Manuel [1, 8, 9]
Número total de Autores: 16
Afiliação do(s) autor(es):
[1] Barretos Canc Hosp, Mol Oncol Res Ctr, BR-14784400 Barretos, SP - Brazil
[2] Barretos Canc Hosp, Dept Pathol, BR-14784400 Barretos, SP - Brazil
[3] Barretos Canc Hosp, Dept Neurosurg, BR-14784400 Barretos, SP - Brazil
[4] AC Camargo Canc Ctr, BR-01508010 Sao Paulo, SP - Brazil
[5] Inst Canc Res, London SW7 3RP - England
[6] Univ Estadual Paulista UNESP, Botucatu Med Sch, Dept Pathol, BR-18618970 Botucatu, SP - Brazil
[7] Barretos Sch Hlth Sci, Dr Paulo Prata FACISB, BR-14785002 Barretos, SP - Brazil
[8] Univ Minho, Sch Med, Life & Hlth Sci Res Inst ICVS, P-4710057 Braga - Portugal
[9] 3Bs PT Govt Associate Lab, P-4806909 Braga - Portugal
Número total de Afiliações: 9
Tipo de documento: Artigo Científico
Fonte: CELLS; v. 9, n. 2 FEB 2020.
Citações Web of Science: 0
Resumo

The 5'-methylthioadenosine phosphorylase (MTAP) gene is located in the chromosomal region 9p21. MTAP deletion is a frequent event in a wide variety of human cancers; however, its biological role in tumorigenesis remains unclear. The purpose of this study was to characterize the MTAP expression profile in a series of gliomas and to associate it with patients' clinicopathological features. Moreover, we sought to evaluate, through glioma gene-edited cell lines, the biological impact of MTAP in gliomas. MTAP expression was evaluated in 507 glioma patients by immunohistochemistry (IHC), and the expression levels were associated with patients' clinicopathological features. Furthermore, an in silico study was undertaken using genomic databases totalizing 350 samples. In glioma cell lines, MTAP was edited, and following MTAP overexpression and knockout (KO), a transcriptome analysis was performed by NanoString Pan-Cancer Pathways panel. Moreover, MTAP's role in glioma cell proliferation, migration, and invasion was evaluated. Homozygous deletion of 9p21 locus was associated with a reduction of MTAP mRNA expression in the TCGA (The Cancer Genome Atlas) - glioblastoma dataset (p < 0.01). In addition, the loss of MTAP expression was markedly high in high-grade gliomas (46.6% of cases) determined by IHC and Western blotting (40% of evaluated cell lines). Reduced MTAP expression was associated with a better prognostic in the adult glioblastoma dataset (p < 0.001). Nine genes associated with five pathways were differentially expressed in MTAP-knockout (KO) cells, with six upregulated and three downregulated in MTAP. Analysis of cell proliferation, migration, and invasion did not show any significant differences between MTAP gene-edited and control cells. Our results integrating data from patients as well as in silico and in vitro models provide evidence towards the lack of strong biological importance of MTAP in gliomas. Despite the frequent loss of MTAP, it seems not to have a clinical impact in survival and does not act as a canonic tumor suppressor gene in gliomas. (AU)

Processo FAPESP: 16/18907-0 - Caracterização do envolvimento da proteína WNK2 no tráfego vesicular autofágico e endocítico em gliomas.
Beneficiário:Ana Laura Vieira Alves
Linha de fomento: Bolsas no Brasil - Mestrado
Processo FAPESP: 17/22305-9 - Estudo de biomarcadores de resposta ao cetuximabe e perspectivas do uso de combi-moléculas anti-EGFR em tumores sólidos
Beneficiário:Izabela Natalia Faria Gomes
Linha de fomento: Bolsas no Brasil - Doutorado
Processo FAPESP: 16/06833-2 - Caracterização molecular de MTAP (Methylthioadenosine phosphorylase) e avaliação do seu potencial terapêutico em gliomas
Beneficiário:Weder Pereira de Menezes
Linha de fomento: Bolsas no Brasil - Doutorado