da Silva Patrícia Benites Gonçalves, Teixeira Dos Santos Márcia Cristina, Rodini Carolina Oliveira, Kaid Carolini, Pereira Márcia Cristina Leite, Furukawa Gabriela, da Cruz Daniel Sanzio Gimenes, Goldfeder Mauricio Barbugiani, Rocha Clarissa Ribeiro Reily, Rosenberg Carla, Okamoto Oswaldo Keith
Centro 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.
Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP, Brazil.
Oncotarget. 2017 Mar 21;8(12):19192-19204. doi: 10.18632/oncotarget.15163.
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.
髓母细胞瘤是一种侵袭性很强的儿童脑肿瘤，最近发现多能性因子OCT4的散在表达与患者预后不良相关。然而，特定OCT4异构体对肿瘤侵袭性的作用仍知之甚少。在此，我们报告稳定过表达OCT4A异构体的髓母细胞瘤细胞表现出增强的克隆形成、肿瘤球生成和侵袭能力。此外，在髓母细胞瘤的原位转移模型中，过表达OCT4A的细胞产生了更发达、侵袭性更强和浸润性更高的肿瘤，荷瘤小鼠出现晚期转移性疾病且生存率更低。促癌性OCT4A的作用依赖于表达水平，并伴有明显的染色体畸变。髓母细胞瘤细胞中OCT4A的过表达还诱导了非编码RNA的显著差异表达，包括特征不明的长链非编码RNA和小核仁RNA。总之，我们的研究结果支持多能性相关因子在加重髓母细胞瘤典型临床预后不良特征中的相关性，并强调了OCT4A在这种具有挑战性的儿童脑癌中的预后和治疗价值。
