NF-kappaB/miR-23a/GSL1通路在鼻咽癌放疗抵抗中的作用及机制研究

Our previous study showed that miR-23a downregulation, upregualtion of its target gene glutaminase 1 (GLS1), and activation of miR-23a trancriptional inhibitor NF-kappaB in the radioresistant nasopharyngeal carcinoma (NPC) cells compared to radiosensitive NPC cells. It is reported that glutamine metabolism is related to cancer radioresistance. Based on these, we hypothesize that NF-kappaB/miR-23a/GLS1 pathway is involved in NPC radioresistance through regulating glutamine metabolism, and then antagonizing oxidative stress excited by irradiation. Therefore, in this project we will analyze (1)the association of NF-kappaB activity, and miR-23a and GLS1 expression with NPC radiosensitivity; (2) whether or not NF-kappaB transcriptionally inhibits miR-23a expression,and whether or not miR-23a targets GLS1 to regulate NPC radiosensivity; (3) whether or not GLS1 upregulation is involved in NPC radioresistance through increasing glutamine metabolism, and then antagonizing oxidative stress excited by irradiation. Our expected data will not only be helpful to reveal the roles and molecular mechanisms of NF-kappaB/miR-23a/GLS1 pathway in NPC radioresistance, but also can provide targets for radiosensitization and targeted therapy of NPC.

我们前期的研究显示：在放疗抵抗鼻咽癌细胞中，miR-23a表达下调， miR-23a靶基因谷氨酰胺酶(GLS1)表达上调，而miR-23a转录抑制因子NK-kappaB显著活化。已有证据显示，谷氨酰胺代谢参与肿瘤放疗抵抗。因此，我们提出"NF-kappaB/miR-23a/GLS1通路调控谷氨酰胺代谢、拮抗放射引起的氧化应激参与鼻咽癌放疗抵抗"的科学假设。为此，项目分析NF-kappaB活性、miR-23a和GLS1表达水平与鼻咽癌放疗敏感性的关系；分析NF-kappaB是否通过转录抑制miR-23a表达以及miR-23a是否通过靶向GLS1调控鼻咽癌的放疗敏感性；分析GLS1上调是否通过增强谷氨酰胺代谢，拮抗放射引起的氧化应激参与鼻咽癌放疗抵抗。项目研究不仅有助于阐明NF-kappaB/miR-23a/GLS1通路在鼻咽癌放疗抵抗中的作用及机制，而且能为鼻咽癌放疗增敏和靶向治疗提供靶标。

鼻咽癌是我国南方常见的恶性肿瘤，严重威胁我国人民的生命和健康。放疗是鼻咽癌的首选治疗手段。放疗抵抗一直是制约鼻咽癌疗效的瓶颈，但鼻咽癌放疗抵抗的分子机制仍然不清楚。我们前期的研究显示：在放疗抵抗鼻咽癌细胞中，miR-23a 表达下调， miR-23a 靶基因谷氨酰胺酶(GLS1)表达上调，而miR-23a 转录抑制因子NK-kappaB 显著活化。因此，我们开展miR-23a以及谷氨酰胺代谢在鼻咽癌放疗抵抗中的作用及其机制研究。主要研究结果如下：(1) 明确了NF-kappaB信号通路激活以及miR-23a表达下调与鼻咽癌放疗抵抗相关；(2) 明确了谷氨酰胺酶(GLS1)高表达以及谷氨酰胺代谢增加鼻咽癌的放疗抵抗性；(3) 发现谷氨酰胺代谢通过激活鼻咽癌细胞自噬促进鼻咽癌放疗抵抗。研究结果表明：GLS1增强谷氨酰胺分解代谢，进而激活鼻咽癌细胞自噬，促进鼻咽癌放疗抵抗；miR-23a、GLS1以及谷氨酰胺代谢有望成为预测鼻咽癌放疗敏感性的标志物以及放疗增敏的靶标。