High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells
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Patrícia Benites Gonçalves da Silva1, Márcia Cristina Teixeira dos Santos1, Carolina Oliveira Rodini1, Carolini Kaid1, Márcia Cristina Leite Pereira1, Gabriela Furukawa1, Daniel Sanzio Gimenes da Cruz2, Mauricio Barbugiani Goldfeder3, Clarissa Ribeiro Reily Rocha4, Carla Rosenberg1, Oswaldo Keith Okamoto1
1Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, Brazil
2Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP, Brazil
3Laboratório de Bioquímica e Biofísica, Instituto Butantan, São Paulo, SP, Brazil
4Departmento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brazil
Oswaldo Keith Okamoto, email: [email protected]
Keywords: OCT4A, POU5F1, LIN28A, medulloblastoma, aggressiveness
Received: May 26, 2016 Accepted: January 22, 2017 Published: February 07, 2017
Medulloblastoma is a highly aggressive pediatric brain tumor, in which sporadic expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However the contribution of specific OCT4 isoforms to tumor aggressiveness is still poorly understood. Here, we report that medulloblastoma cells stably overexpressing the OCT4A isoform displayed enhanced clonogenic, tumorsphere generation, and invasion capabilities. Moreover, in an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic OCT4A effects were expression-level dependent and accompanied by distinct chromosomal aberrations. OCT4A overexpression in medulloblastoma cells also induced a marked differential expression of non-coding RNAs, including poorly characterized long non-coding RNAs and small nucleolar RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer.
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