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A Transcriptomic Signature Mediated by HOXA9 Promotes Human Glioblastoma Initiation, Aggressiveness and Resistance to Temozolomide

Marta Pojo a,b, Céline S. Gonçalves a,b, Ana Xavier-Magalhães a,b, Ana Isabel Oliveira a,b, Tiago Gonçalves a,b, Sara Correia c, Ana J. Rodrigues a,b, Sandra Costa a,b, Luísa Pinto a,b, Afonso A. Pinto d, José M. Lopes e,f,g, Rui M. Reis a,b,h, Miguel Rocha c, Nuno Sousa a,b, Bruno M. Costa a,b

aLife and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar 4710-057 Braga, Portugal; bICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Campus de Gualtar 4710-057 Braga, Portugal; cCentre of Biological Engineering/Department of Informatics, University of Minho, Campus de Gualtar 4710-057 Braga, Portugal; dDepartment of Neurosurgery, Hospital de Braga, Sete Fontes, 4710-243 São Victor, Braga, Portugal; eDepartment of Pathology, Hospital S. João, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; fInstitute of Molecular Pathology and Immunology at the University of Porto (IPATIMUP), Rua Dr. Roberto Frias s/n 4200-465 Porto, Portugal; gMedical Faculty, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; hBarretos Cancer Hospital, Molecular Oncology Research Center, Rua Antenor Duarte Vilela, 1331 - Doutor Paulo Prata, Barretos - SP, 14780-000, Brasil.

Glioblastoma is the most common and malignant subtype of glioma, exhibiting remarkable resistance to treatment. Here we investigated the oncogenic potential of HOXA9 in gliomagenesis, the molecular and cellular mechanisms by which HOXA9 may render glioblastoma more aggressive, and how HOXA9 affects response to chemotherapy.
Expression microarrays were used to identify HOXA9 target genes. Stable glioblastoma cell lines with ectopic HOXA9 overexpression or shRNA-mediated knockdown of HOXA9 were established to evaluate the roles of HOXA9 in cell viability, death, invasion, and response to temozolomide. Subcutaneous and orthotopic xenograft models of glioblastoma were established to evaluate the oncogenic potential of HOXA9 in vivo, and its role in response to temozolomide and overall survival.
Transcriptomic analyses identified novel HOXA9-target genes that have key roles in critical cancer processes. Functional assays with a variety of glioblastoma cells revealed that HOXA9 promotes cell viability, stemness, and invasion; conversely, HOXA9 displayed anti-apoptotic functions. Additionally, ectopic expression of HOXA9 promoted the malignant transformation of human immortalized astrocytes in an intracranial orthotopic mouse model of glioblastoma, and caused tumor-associated death. HOXA9 also mediated resistance to temozolomide treatment both in vitro and in vivo. Mechanistically, BCL2 was identified as a novel HOXA9 target that may be therapeutically targeted. Indeed, the pharmacological inhibition of BCL2 with ABT-737 specifically reverted temozolomide resistance in HOXA9-positive cells.
These data establish HOXA9 as a critical driver of glioma initiation, aggressiveness and resistance to therapy.

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