High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells.
High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells.
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DOI：
10.18632/oncotarget.15163
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发表时间：
2017-03-21
期刊：
影响因子：
--
通讯作者：
Okamoto OK
中科院分区：
文献类型：
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作者：
da Silva PBG;Teixeira Dos Santos MC;Rodini CO;Kaid C;Pereira MCL;Furukawa G;da Cruz DSG;Goldfeder MB;Rocha CRR;Rosenberg C;Okamoto OK
髓母细胞瘤是一种高度侵袭性的儿童脑瘤，其中多能因子OCT4的零星表达最近被认为与患者的生存不良有关。然而，特定的OCT4亚型对肿瘤侵袭性的贡献仍然知之甚少。在这里，我们报告了稳定高表达Oct4A亚型的髓母细胞瘤细胞表现出更强的克隆形成、肿瘤球体生成和侵袭能力。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、更具侵袭性和浸润性的肿瘤，荷瘤小鼠获得了晚期转移疾病和较短的存活率。致癌基因Oct4A的作用是表达水平依赖的，并伴随着明显的染色体异常。Oct4A在髓母细胞瘤细胞中的过表达也诱导了非编码RNA的显著差异表达，包括特征不佳的长非编码RNA和小核仁RNA。总之，我们的发现支持多潜能相关因素在髓母细胞瘤特征加重中的相关性，这些特征通常与不良的临床结果有关，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。
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.