High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells

// Patricia Benites Goncalves da Silva 1 , Marcia Cristina Teixeira dos Santos 1 , Carolina Oliveira Rodini 1 , Carolini Kaid 1 , Marcia Cristina Leite Pereira 1 , Gabriela Furukawa 1 , Daniel Sanzio Gimenes da Cruz 2 , Mauricio Barbugiani Goldfeder 3 , Clarissa Ribeiro Reily Rocha 4 , Carla Rosenberg 1 , Oswaldo Keith Okamoto 1 1 Centro de Pesquisa sobre o Genoma Humano e Celulas-Tronco, Departamento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de Sao Paulo, Sao Paulo, SP, Brazil 2 Departamento de Patologia, Faculdade de Medicina Veterinaria e Zootecnia, Universidade de Sao Paulo, Sao Paulo, SP, Brazil 3 Laboratorio de Bioquimica e Biofisica, Instituto Butantan, Sao Paulo, SP, Brazil 4 Departmento de Microbiologia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP, Brazil Correspondence to: Oswaldo Keith Okamoto, email: keith.okamoto@usp.br Keywords: OCT4A, POU5F1, LIN28A, medulloblastoma, aggressiveness Received: May 26, 2016      Accepted: January 22, 2017      Published: February 07, 2017 ABSTRACT 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.