长链非编码RNA调控网络在脑胶质瘤替莫唑胺耐药中的作用与机制

Glioma is the malignant central nervous system tumor with high incidence and mortality. Chemotherapy resistance of temozolomide (TMZ) is increasingly recognized as a critical obstacle for glioma treatment. Long non-coding RNAs (lncRNAs) play important roles in the transcriptional regulation and are closely related to the growth, invasion and metastasis of malignant tumors. However, the exact roles of lncRNAs in the TMZ resistance of glioma are still unknown. In our previous study, using lncRNA sequencing technique, we have identified a number of abnormally expressed lncRNAs between T98G and TMZ-resistance T98G glioma cells. Additionally, we have found a reduced level of autophagy in TMZ-resistance T98G glioma cells. The aim of this subject is further to indentify lncRNAs relating to TMZ-resistance, characterize the molecular mechanisms of the lncRNAs on the regulation of gene expression and signal transduction, and investigate the underlying effect of lncRNAs in autophagy in tumor cells. This study may help to reveal the mechanisms of TMZ-resistance, and provide potential therapeutic targets to TMZ-resistant glioma.

脑胶质瘤是高度恶性、高致死率的中枢神经系统肿瘤。替莫唑胺（TMZ）治疗脑胶质瘤出现化疗耐药是亟待解决的重要临床问题。长非编码RNA（lncRNA）在转录组中占有重要地位，与恶性肿瘤生长、侵袭、转移密切相关，然而其在脑胶质瘤TMZ耐药的作用与机制研究还未有报道。前期研究中，通过转录组测序和lncRNA测序我们发现，脑胶质瘤细胞和TMZ抵抗的脑胶质瘤细胞之间lncRNA的表达存在差异性改变，且TMZ抵抗细胞系自噬水平明显降低。本课题拟在前期发现的基础上，进一步筛选、鉴定在脑胶质瘤TMZ耐药中发挥重要作用的lncRNAs，探讨lncRNAs的互作分子，并深入研究这些lncRNAs在肿瘤细胞中基因调控和信号转导的具体分子机制，探索其在肿瘤自噬中的作用。本课题有助于揭示脑胶质瘤TMZ耐药的机理，同时将为脑胶质瘤TMZ抵抗患者的治疗提供新的分子标志和治疗靶标。

胶质母细胞瘤（GBM）是一种侵袭性星形细胞肿瘤，其发病率和致死率是神经系统肿瘤的首位。替莫唑胺（TMZ）是用于治疗GBM使用最广泛、最有效的一线化疗药物。然而，临床患者长期使用TMZ，GBM细胞对TMZ引起的细胞毒性易发生耐药，导致药物疗效及安全性的下降。本研究发现ADAMTS9-AS2可通过上调胶质瘤细胞的FUS/MDM2轴促进TMZ耐药。其分子机制是由ADAMTS9-AS2通过与MDM2竞争性结合FUS的RRM或Znf_RanBP2结构域，抑制MDM2依赖的FUS K48泛素化，增强FUS的稳定性，促进TMZ耐药。我们的结果提示ADAMTS9-AS2/ FUS/MDM2轴是胶质瘤TMZ耐药治疗的潜在靶点。本研究首次确认了ADAMTS9-AS2是调控FUS的关键因子，可作为增强胶质瘤TMZ敏感性的潜在靶点。