MicroRNA-195在人脑胶质瘤替莫唑胺化疗耐药中的作用及机制研究

Alkylating agent Temozolomide is currently the first-line chemotherapy drug for initial and recurrent glioma treatment with the best clinical efficacy, which exerts its antitumor effects mainly through cell death induced by DNA double-strand breaks in G1 and S phase. However, endogenous or acquired resistance to TMZ limits GBM patients' clinical outcome as well as an important cause of GBM replase. MicroRNA-195 (miR-195) plays an important role in the regulation of G1/S phase transition and DNA damage repair and proliferation and apoptosis of tumor cells. Our previous studies have shown that miR-195 is down-regulated in human malignant gliomas and glioma cell lines, which acts as a candidate tumor suppressor gene, an independent predictor of overall survival. Therefore, we hypothesized that miR-195 may be closely associated with temozolomide-acquired resistance of glioblastoma. we We found that overexpression of miR-195 can inhibit glioma cell proliferation and promote cell apoptosis. In addition, we found that miR-195 expression was further reduced in temozolomide-resistant glioblastoma cells induced stepwisely with TMZ, negatively correlated to the resistance index. On the basis of previous studies, this study will investigate the relationship between the expression of miR-195 and TMZ resistance of glioma cell, explore the effect of miR-195 on the biological behaviors of TMZ-resistant variants and the possible molecular mechanism. These findings of this study will help to further understand the biological function of miR-195 and TMZ resistance mechanism, which helps neurosurgeon predict TMZ treatment effect. Furthermore, establishment of miR-195 interventions will reverse or restore sensitivity to temozolomide of glioma cells.

替莫唑胺（TMZ）是目前国内外治疗胶质瘤的首选药物，主要在G1晚期、S早期损伤DNA诱导肿瘤细胞凋亡，但耐药性的产生严重限制了患者的获益程度。研究表明，miR-195在调控细胞周期G1/S转换，DNA损伤修复，细胞增殖凋亡中发挥着关键作用。因此，我们推测miR-195可能与胶质瘤对TMZ形成耐药关系密切。课题组前期研究初步证实这一推测，miR-195不仅在胶质瘤组织及细胞中低表达，而且在胶质瘤TMZ耐药株中表达进一步下调。本研究将在此研究基础上，分析miR-195的表达与胶质瘤TMZ耐药产生的相关性，系统探讨miR-195对胶质瘤耐药株细胞的生物学行为的影响，进而研究miR-195影响胶质瘤细胞耐药性的可能分子机制，这将有助于深入理解miR-195的生物学作用及胶质瘤对TMZ耐药性形成机制，预测TMZ治疗效果，同时建立针对miR-195的干预措施，有望恢复耐药细胞的敏感性。