HIF1A is Overexpressed in Medulloblastoma and its Inhibition Reduces Proliferation and Increases EPAS1 and ATG16L1 Methylation

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Veiga Cruzeiro, Gustavo Alencastro ^[1] ; dos Reis, Maristella Bergamo ^[2] ; Silveira, Vanessa Silva ^[1] ; Peixoto Lira, Regia Caroline ^[2] ; Carlotti, Carlos Gilberto ^[3] ; Neder, Luciano ^[3] ; Oliveira, Ricardo Santos ^[3] ; Yunes, Jose Andres ^{[4, 5, 6]} ; Brandalise, Silvia Regina ^{[4, 5, 6]} ; Aguiar, Simone ^{[4, 5]} ; Eterovic, Agda Karina ^[7] ; Tone, Luiz Gonzaga ^[1] ; Scrideli, Carlos Alberto ^[2] ; Valera, Elvis Terci ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pediat, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Surg, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[4] Ctr Infantil Boldrini, Rua Dr Gabriel Porto 1270, BR-13083210 Campinas, SP - Brazil

^[5] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pathol, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[6] Univ Estadual Campinas, Cidade Univ Zeferino Vaz Barao Geraldo, BR-13083970 Campinas, SP - Brazil

^[7] Univ Texas MD Anderson Canc Ctr, Inst Personalized Canc Therapy, Houston, TX 77030 - USA

• Tipo de documento: Artigo Científico
• Fonte: CURRENT CANCER DRUG TARGETS; v. 18, n. 3, p. 287-294, 2018.
• Citações Web of Science: 4

Resumo

Background: Genetic and epigenetic modifications are closely related to tumor initiation and progression and can provide guidance for understanding tumor functioning, potentially leading to the discovery of new therapies. Studies have associated hypoxia-related genes to tumor progression and chemo/radioresistance in brain tumors. Information on the expression profile of hypoxia-related genes in pediatric medulloblastoma, although scarce, may reveal relevant information that could support treatment decisions. Objective: Our study focused on evaluation the of CA9, CA12, HIF1A, EPAS1, SCL2A1 and VEGF genes in 41 pediatric fresh-frozen medulloblastoma sample. Additionally, we analyzed the effect of hypoxia and normoxia in the pediatric medulloblastoma cell-line UW402. Furthermore, we assessed the effects of HIF1A knockdown in cell-proliferation and methylation levels of genes related to hypoxia, apoptosis and autophagy. Method: qPCR was performed to evaluate mRNA levels, and Western blot to confirm HIF1A silencing in both patient samples and cell line. Pyrosequencing was performed to asses the methylation levels after HIF1A knockdown in the UW402 cell line. Results: A higher HIF1A mRNA level was observed in MB patients when compared to the cerebellum (non-tumor match). In UW402 MB cell-line, chemically induced hypoxic resulted in an increase of mRNA levels of HIF1A, VEGF, SCL2A1 and CA9 genes. Additionally, HIF1A knockdown induced a decrease in the expression of hypoxia related genes and a decrease of 30% in cell proliferation was also observed. Also, a significant increase in the methylation of ATG16L1 promoter and decrease in the methylation of EPAS1 promoter were observed after HIF1A knockdown. Conclusion: HIF1A knockdown in medulloblastoma cells lead to decreased cellular proliferation, suggesting that HIF1A can be a potential therapeutic target to be explored in the medulloblastoma. However, the mechanisms behind HIF1A protein stabilization and function are very complex and more data need to be generated to potentially use HIF1A as a therapeutical target. (AU)

• Processo FAPESP: 12/06592-4 - Investigação de mecanismos epigenéticos regulados por HIF1A e seus alvos transcritos em linhagem de meduloblastoma exposta ao ambiente de hipóxia
• Beneficiário: Gustavo Alencastro Veiga Cruzeiro
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Mestrado
• Processo FAPESP: 11/04682-3 - Silenciamento do gene HIF1A em linhagem de meduloblastoma exposta ao ambiente de hipóxia
• Beneficiário: Gustavo Alencastro Veiga Cruzeiro
• Modalidade de apoio: Bolsas no Brasil - Mestrado