c-Myc激活长非编码RNA- MALAT1促进胶质母细胞瘤对替莫唑胺耐药的机制研究

Temozolomide (TMZ) is the first-line chemotherapy drug for glioblastoma (GBM), but its resistance directly influence the curative effect. Our team have already published that non-coding RNA - MALAT1 plays a key role in TMZ resistance on GBM. But its upstream key regulatory genes and their mechanism is still unclear. Our preliminary results show that MALAT1 may be activated by c-Myc and promote GBM to TMZ resistance: there are three potential c-Myc binding sites in MALAT1 promoter area; MALAT1 is upregulated after overexpression of c-Myc; the expression of these two genes in TMZ resistant GBM clinical samples were positively correlated. This project intends to explore whether c-Myc is combined with MALAT1 promoter and identify their binding sites; To understand whether MALAT1 promote the TMZ resistance on GBM is dependent on c-Myc transcription regulation; Explore whether to test the two genes in the GBM clinical samples can help to better determine its resistance to TMZ. Project completion will not only clarify the c-Myc/MALAT1 in GBM for the key role of TMZ resistance and its molecular mechanism, and also provides new theoretical basis for clinical drug resistance evaluation and development of new treatments.

替莫唑胺（TMZ）是胶质母细胞瘤（GBM）的一线化疗药物，但其耐药性直接影响疗效。我们团队已报道：非编码RNA-MALAT1(本项目称MALAT1)高表达在GBM对TMZ耐药中起关键作用。但其上游关键调控基因及其机制尚不清楚。我们的预实验表明：MALAT1启动子结合区有三个潜在c-Myc结合位点；过表达c-Myc可上调MALAT1；TMZ耐药的GBM临床样本中这两者的表达呈正相关。这些结果提示c-Myc可能激活MALAT1而促进GBM对TMZ耐药。本项目拟明确c-Myc与MALAT1启动子结合并鉴定其结合位点；研究MALAT1促进GBM对TMZ的耐药是否依赖于c-Myc的转录调控；探讨GBM临床样本中检测这两者是否更好判断其对TMZ的耐药性。本项目的完成不仅可揭示c-Myc/MALAT1在GBM对TMZ耐药中的关键作用及其分子机制，还可为临床耐药评估和新型治疗手段的研制提供新的理论基础。

本课题针对临床中GBM对TMZ耐药这一重要问题，以长非编码RNA为研究切入点，通过高通量测序及临床标本验证的方法，探讨了长非编码RNA-MALAT1异常高表达在GBM对TMZ产生耐药性中的关键作用。本项目提出并初步验证了“原癌基因c-Myc转录激活长非编码RNA-MALAT1促进GBM对TMZ产生耐药”的假说。通过本项目的实验分析，我科初步证明了非编码RNA-MALAT1的启动子区与c-Myc之间可能存在三个结合位点，MALAT1促进GBM对TMZ的耐药可能依赖于c-Myc的转录调控等科学问题，初步阐明导致TMZ耐药的关键分子MALAT1表达异常的具体转录起始结合位点，揭示了c-Myc/MALAT1在GBM对TMZ耐药中的关键作用，有望为临床耐药评估和新型治疗手段的研制提供新的理论基础。