LINC00518/HIF-1α正反馈环调控糖酵解促进黑色素瘤放射抵抗的机制研究

Radioresistance is the major obstacle that limits radiotherapy of melanoma. Our previous studies showed that miR-33a-3p could increase radiosensitivity of melanoma by targeting HIF-1α, LINC00518 might bind with miR-33a-3p directly, and HIF-1α might upregulate the expression of LINC00518 through direct and indirect mechanisms. In this study, we focus on the idea that LINC00518/HIF-1α positive feedback loop can up-regulate glycolytic levels in melanoma to promote tumor radioresistance. Firstly, we confirm the relationship between LINC00518/HIF-1α positive feedback loop.Secondly, we further investigate the detail molecular mechanisms of LINC00518/HIF-1α positive feedback loop regulating glycolytic levels and radiosensitivity of melanoma cells. In addition, animal models are performed to validate the effects in vivo. Finally we will verify the predictive value of LINC00518, miR-33a-3p, HIF-1α and the glycolysis related factors in tissues for the melanoma patients received radiotherapy by analyzing the collected clinical samples. Through these, above signaling and glycolysis related genes may serve as valuable prognostic markers, and would provide scientific evidence for development of novel radiosensitizers and individualized radiotherapeutic regimen of melanoma.

放射抵抗是限制黑色素瘤放射治疗疗效的瓶颈。我们前期研究表明，miR-33a-3p靶向抑制HIF-1α来增加黑色素瘤放射敏感性，而LINC00518靶向抑制miR-33a-3p，HIF-1α却可直接或间接正反馈调控LINC00518的表达。综合这些研究，表明黑色素瘤中LINC00518与HIF-1α之间存在正反馈调控环。因此，申请者以LINC00518/HIF-1α正反馈环调控糖酵解水平来促进肿瘤细胞放射抵抗为主轴，拟从分子、细胞及动物水平，探讨正反馈环-黑色素瘤糖酵解水平-放射抵抗之间的深层关系，并行功能回复实验加以验证，最后利用现有的临床标本及资料，测定患者组织中LINC00518、HIF-1α等基因表达水平及糖酵解表型的临床价值。力争为临床上黑色素瘤放射治疗提供新靶点，为患者个体化方案提供新思路。

放射抵抗是限制黑色素瘤放射治疗疗效的瓶颈，本研究紧扣这一亟待解决的临床难题，原创性的证实了LINC01588在黑色素瘤中高表达，其高表达与黑色素瘤患者预后不良正相关；功能上，通过体内外实验证实LINC01588可显著增强黑色素瘤细胞糖酵解水平和放射抵抗；机制上，证实了LINC00518可与HIF-1α形成反馈环路，从而调控糖酵解水平来促进肿瘤 细胞放射抵抗。在本项目资助下，我们的直接研究及拓展研究共发表SCI论文26篇；获得中国发明型及实用型专利7项，软件著作权1项；参编专著1部，获批国家或省部级课题10余项，获湖南省自然科学奖二等奖、湖南省医学科技进步奖一等奖等多项奖励。荣获湖南省科技创新领军人才（2020）、湖南省芙蓉青年学者（2020）、湖南省科技人才托举工程（2019）等。为临床上黑色素瘤等恶性肿瘤放疗增敏剂的研发及临床应用提供了新证据和新思路，具有一定的临床实用性及开发潜能。