de Sousa Juliana Ferreira, Torrieri Raul, Serafim Rodolfo Bortolozo, Di Cristofaro Luis Fernando Macedo, Escanfella Fábio Dalbon, Ribeiro Rodrigo, Zanette Dalila Lucíola, Paçó-Larson Maria Luisa, da Silva Wilson Araujo, Tirapelli Daniela Pretti da Cunha, Neder Luciano, Carlotti Carlos Gilberto, Valente Valeria
1 Department of Clinical Analysis, Faculty of Pharmaceutical Sciences of Araraquara, University of São Paulo State, Araraquara, Brazil.
2 Department of Cellular and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil.
Tumour Biol. 2017 Apr;39(4):1010428317694552. doi: 10.1177/1010428317694552.
Astrocytomas are the most common primary brain tumors. They are very resistant to therapies and usually progress rapidly to high-grade lesions. Here, we investigated the potential role of DNA repair genes in astrocytoma progression and resistance. To this aim, we performed a polymerase chain reaction array-based analysis focused on DNA repair genes and searched for correlations between expression patters and survival prognoses. We found 19 genes significantly altered. Combining these genes in all possible arrangements, we found 421 expression signatures strongly associated with poor survival. Importantly, five genes (DDB2, EXO1, NEIL3, BRCA2, and BRIP1) were independently correlated with worse prognoses, revealing single-gene signatures. Moreover, silencing of EXO1, which is remarkably overexpressed, promoted faster restoration of double-strand breaks, while NEIL3 knockdown, also highly overexpressed, caused an increment in DNA damage and cell death after irradiation of glioblastoma cells. These results disclose the importance of DNA repair pathways for the maintenance of genomic stability of high-grade astrocytomas and suggest that EXO1 and NEIL3 overexpression confers more efficiency for double-strand break repair and resistance to reactive oxygen species, respectively. Thereby, we highlight these two genes as potentially related with tumor aggressiveness and promising candidates as novel therapeutic targets.
星形细胞瘤是最常见的原发性脑肿瘤。它们对治疗具有很强的抗性，通常会迅速发展为高级别病变。在此，我们研究了DNA修复基因在星形细胞瘤进展和抗性中的潜在作用。为此，我们进行了一项基于聚合酶链反应阵列的分析，重点关注DNA修复基因，并寻找表达模式与生存预后之间的相关性。我们发现19个基因发生了显著改变。将这些基因以所有可能的组合方式进行组合，我们发现421种表达特征与不良生存密切相关。重要的是，五个基因（DDB2、EXO1、NEIL3、BRCA2和BRIP1）与较差的预后独立相关，揭示了单基因特征。此外，显著过表达的EXO1的沉默促进了双链断裂的更快修复，而同样高度过表达的NEIL3的敲低导致胶质母细胞瘤细胞照射后DNA损伤增加和细胞死亡。这些结果揭示了DNA修复途径对于维持高级别星形细胞瘤基因组稳定性的重要性，并表明EXO1和NEIL3的过表达分别赋予了双链断裂修复更高的效率和对活性氧的抗性。因此，我们强调这两个基因可能与肿瘤侵袭性相关，并且有望成为新的治疗靶点。
