IDH1突变通过抑制Nrf2-ARE抗氧化应激通路敏化胶质瘤化疗的分子机制研究

Recent years, many studies have shown that patients with glioma that carrying IDH1 (isocitrate dehydrogenase 1) mutation are more sensitivity to chemotherapy. However, relevant molecular mechanism is still vague. Our preliminary study suggests that compared with the wild-type, IDH1 mutation inhibits Nrf2-ARE endogenous antioxidant stress pathway significantly, and increases intracellular ROS significantly. Further, we found that the expression of Nrf2 is modulate post-transcriptionally via analyzing the expression pattern. To analyze the expression profile of miRNA, we found that IDH1 mutation increases the expression level of miR-340 significantly which targets to Nrf2. Hence, we put forward new mechanism of enhancing chemosensitivity by the mutation of IDH1 in glioma, namely, miR-340 suppresses Nrf2 and its downstream antioxidant stress signaling pathway, leads to accumulation of ROS which is induced by chemotherapy, thus sensitizes glioma to chemotherapy. In this study, research will be performed to validate the importance of Nrf2-ARE antioxidant stress pathway to the chemosensitivity of glioma with IDH1 mutation. Moreover, experiments will be performed to clarify the mechanism of IDH1 mutation inhibits Nrf2-ARE pathway via modulating the expression of miR-340. To provide new idea of improving the chemosensitivity of glioma, thus guide precision medicine.

近年来大量研究发现携带IDH1（异柠檬酸脱氢酶1）突变基因的胶质瘤患者对化疗更加敏感，但其分子机制仍不明确。课题组前期研究提示，与野生型相比，突变型胶质瘤中Nrf2-ARE内源性抗氧化应激通路受到显著抑制，细胞内ROS水平显著增高。进一步分析Nrf2的表达，提示Nrf2表达受转录后调控，因此，我们分析miRNA的表达谱，发现突变型胶质瘤miR-340表达显著增高，且Nrf2为其靶基因。由此，我们提出IDH1突变敏化化疗的新机制，即：IDH1突变通过miR-340调控Nrf2及其下游抗氧化蛋白和II相解毒酶，导致化疗诱导的ROS积聚，增加化疗敏感性。本研究拟通过功能实验明确Nrf2-ARE信号通路在IDH1突变敏化化疗中的机制；阐明IDH1突变通过调节miR-340的表达进而影响Nrf2-ARE信号通路的机制。为改善胶质瘤化疗敏感性提供新的思路，指导临床精准治疗。

胶质瘤是最常见的颅内原发性肿瘤，约占神经上皮性肿瘤60%，具有发病率、复发率、死亡率高和治愈率低“三高一低”的特点。近年来大量研究发现携带IDH1突变基因的胶质瘤患者对替莫唑胺化疗更加敏感，具有更好的临床预后，但相关的分子机制仍不明确。本研究证明Nrf2-ARE抗氧化应激信号通路在IDH1突变敏化胶质瘤替莫唑胺治疗中的重要作用，阐明IDH1突变在敏化胶质瘤替莫唑胺化疗中的作用途径，为预测胶质瘤替莫唑胺化疗敏感性提供新的思路和理论依据。有利于进一步改善胶质瘤替莫唑胺化疗敏感性，为胶质瘤精准治疗开辟新领域。通过临床标本分析，Nrf2可能成为预测胶质瘤替莫唑胺化疗敏感性的因素，有利于指导临床精准治疗。