JNK活化FOXO3a在胶质母细胞瘤放疗抵抗中的作用及其机制研究

Radio-resistance directly impacts the survival and living quality of patients with glioblastoma (GBM), which makes the molecular mechanism behind, and the way to improve radio-resistance an ongoing key but ticklish topic in neuro-oncology. Previously, we found a close association between the expression of FOXO3a and the survival of patients in GBM samples, and confirmed that FOXO3a contributed to the development and progress of GBM significantly, and participated in the resistance against temozolomide of GBM. A further investigation revealed that radiation increased the expression of FOXO3a，whereas knockdown of FOXO3a expression increased both DNA double-strand breaks and GBM cell apoptosis. As the key downstream molecule of JNK pathway, the expression of both increased obviously in samples from recurrent GBM tissues. Moreover, overexpression of FOXO3a up-regulated the transcription of integrin-linked kinase (ILK).Taken together, we hypothesize that in the course of radiotherapy for GBM, JNK activates FOXO3a, which in turn up-regulates the expression of ILK, thereby causing the activation of PI3K/AKT pathway, and eventually giving rise to radio-resistance of GBM. To confirm this hypothesis, we will carry out verification in clinical samples as well as cell- and animal-based assays on the function and mechanism of JNK-activated FOXO3a in radio-resistance of glioblastoma, and thus will provide researchers with a novel thinking in the improvement of sensitization of GBM to radio-therapy.

放疗抵抗直接影响胶质母细胞瘤（GBM）患者的生存期，深入研究放疗抵抗产生的分子机制，提升治疗效果一直是神经肿瘤学领域研究的重点和难点。我们曾报道GBM标本中FOXO3a表达量与患者生存期密切相关，并证实其是GBM发生发展的重要因子且参与替莫唑胺治疗耐受。进一步研究发现，放射可引起FOXO3a表达增高，敲低FOXO3a表达后可增加放射造成的细胞凋亡及DNA双链断裂；FOXO3a是JNK信号下游分子，在复发的GBM标本中二者表达均增高；且FOXO3a过表达后会引起整合素连接激酶（ILK）转录上调。据此，我们推断在GBM放疗过程中JNK升高可引起FOXO3a活化，活化的FOXO3a进一步促进ILK的表达来增强PI3K/AKT通路活性，从而导致放疗抵抗。为了证实该假说，我们将通过临床标本、细胞学和动物实验来阐明FOXO3a对GBM放疗抵抗的作用及其分子机制，从而为GBM的放疗增敏提供新思路。

放疗抵抗直接影响胶质母细胞瘤（GBM）患者的生存期，深入研究放疗抵抗产生的分子机制，提升治疗效果一直是神经肿瘤学领域研究的重点和难点。我们在前期研究中发现GBM标本中FOXO3a表达量与患者生存密切相关，并证实其是GBM发生发展的重要因子且参与替莫唑胺的治疗耐受。本项目研究发现，辐照可引起FOXO3a表达增高；敲低FOXO3a表达后辐照造成的细胞凋亡及DNA损伤增加；动物实验进一步证明FOXO3a表达量与放疗抵抗关系密切。不仅如此，机制研究发现GBM放疗过程中JNK升高可引起FOXO3a活化，活化的FOXO3a进一步促进ILK的表达来增强PI3K/AKT通路活性，从而导致放疗抵抗。在复发的GBM标本中JNK和FOXO3a表达均增高。综上，本项目通过临床标本、细胞学和动物实验阐明FOXO3a在GBM放疗抵抗的作用及其分子机制，研究结果为GBM的放疗增敏提供新的思路。