长链非编码RNA-GAS5通过一组增殖相关microRNAs调控胶质母细胞瘤增殖的作用及机制研究

Glioblastoma (GBM) is the most common brain tumor with the characteristics of unlimited fast proliferation. According to recent studies, LncRNAs, mRNA-like transcripts ranging in length from 200 nucleotides (nt) to 100 kilobases (kb) without protein-coding abilities, are emerging as the new important players in pathogenesis and malignant proliferation of GBM, but it is still not clear in the mechanisms that LncRNAs inhibit the malignant proliferation of GBM. Our previous study showed that the expression of growth arrest-specific 5 (GAS5) was negatively correlated with prognosis of patients with GBM and GAS5 may function as a decoy/endogenous “sponge” for proliferation-related microRNAs (miRs) to inhibit miRs expression and GBM proliferation. That’s why we propose that GAS5 inhibit proliferation of GBM via regulating proliferative-related miRs and its targeted genes with vital function in GBM proliferation. In this study, we will investigate the effects of GAS5 on the proliferation of GBM cell lines in vivo and tumorigenicity in vitro. Then we will further focus on the molecular mechanism that GAS5 play its regulatory role in the tumor proliferation by acting as an endogenous “sponge” for miRs which had been proved to be related with proliferation of GBM. Moreover, we will examine the expression patterns of GAS5, miRs regulated by GAS5, miRs targeted genes and Ki67 in specimen of GBM patients and analyze the relationship between miRs, miRs targeted genes, Ki67 and GAS5 and the correlation between the expression of these molecules and the prognosis of GBM patients. This study will provide more evidence to fully understand the regulatory role of lncRNAs on proliferation of GBM and the theoretical and practical basis for the establishment of lncRNAs-mediated therapeutic manipulation on GBM to improve the quality of life and overall survival of GBM patients.

胶质母细胞瘤（GBM）是最常见脑肿瘤，恶性程度高，具有快速增殖特点。研究表明，在其发生发展及恶性增殖调控中长链非编码RNAs （Lnc-RNAs）至关重要，但其分子机制仍不清楚。我们研究发现：抑癌基因LncRNA-生长停滞敏感基因5（GAS5）与GBM患者预后密切相关，且GAS5可抑制GBM增殖并抑制增殖相关miRs的表达。故我们推测GAS5通过调控增殖相关miRs及其靶分子抑制GBM的增殖。本课题拟在前期工作基础上，从体内体外水平研究GAS5对GBM增殖的影响；进而阐明GAS5通过调控增殖相关miRs及其下游靶基因抑制GBM增殖的分子机制；结合临床资料，在肿瘤标本中分析GAS5与受其调控的miRs和下游靶分子的相关性及其与GBM增殖的相关性，并分析上述分子与GBM患者预后的相关性。这对阐明GBM增殖的新分子机制、建立有效治疗靶点、提高患者生存时间、改善生存质量具有重要意义。