GM-CSF在鼻咽癌放疗抵抗中的作用及其机制研究

We used an antibody array to compare the expression difference of cytokines secreted by radioresistant and radiosensitive nasopharyngeal carcinoma (NPC) cell lines, and found that the high secretion and overexpression of GM-CSF are associated with NPC radioresistance. To further investigate for the roles and molecular mechanisms of GM-CSF in the NPC radioresistance, in this project NPC cell lines with the GM-CSF expressional and secretory changes will be established; the effects of GM-CSF expression and secretory changes on the NPC cell radiosensitivity in vitro and in vivo will be determined; the activities of AKT, Stat3 and ERK-1/2 signaling pathways as well as the association of theses signaling pathways activities with NPC radioresistance will be analyzed in the transfected NPC cell lines, which can elucidate the roles of GM-CSF-activating signal pathways in NPC radioresistance; finally the association of GM-CSF levels in NPC tissues and patients serums with tumor radioresistance will be analyzed to explore if GM-CSF can serve as biomarker for predicting NPC radiosensitivity. Our expected results will not only be helpful to reveal the role and mechanisms of GM-CSF in NPC radioresistance, but also be provide the targets for predicting NPC radiosensitivity and targeted and personalized therapy of NPC. Moreover, our data will indicate that NPC patients should be given GM-CSF cautiously to prevent and treat leucopenia induced by radiotherapy.

我们前期采用抗体芯片比较放疗抵抗与放疗敏感鼻咽癌细胞分泌的炎性细胞因子的差异，发现粒细胞-巨噬细胞集落刺激因子(GM-CSF)高分泌/高表达与鼻咽癌放疗抵抗密切相关。为揭示GM-CSF在鼻咽癌放疗抵抗中的作用及其机制，项目拟建立GM-CSF表达和分泌改变的鼻咽癌细胞系，分析GM-CSF对体外和体内鼻咽癌放疗敏感性的影响；然后分析GM-CSF对鼻咽癌细胞AKT、Stat3和ERK-1/2信号通路活性的影响及其与鼻咽癌放疗抵抗的关系，明确GM-CSF增强鼻咽癌放疗抵抗的分子机制；最后分析血清和组织GM-CSF水平与鼻咽癌放疗抵抗性的关系，探讨GM-CSF是否可作为预测鼻咽癌放疗敏感性的标志物。项目研究不仅有助于揭示GM-CSF在鼻咽癌放疗抵抗中的作用及其机制，而且能为鼻咽癌的放疗敏感性预测以及鼻咽癌的靶向治疗和个体化放疗提供靶标，并可警示鼻咽癌患者应慎用GM-CSF防治放疗所致的白细胞减少症。

我们前期采用抗体芯片比较放疗抵抗与放疗敏感鼻咽癌细胞分泌的炎性细胞因子的差异，发现粒细胞-巨噬细胞集落刺激因子(GM-CSF)在放疗抵抗鼻咽癌细胞中高表达。然而，GM-CSF在肿瘤放疗抵抗中的作用及其机制不清楚。为此，项目开展GM-CSF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)建立了GM-CSF过表达和敲低的稳定转染鼻咽癌细胞系，利用建立的稳定转染细胞系，证实GM-CSF显著增加体外和体内鼻咽癌细胞的放疗抵抗性；(2)明确了GM-CSF通过Lyn激活鼻咽癌细胞的AKT、Stat3和ERK1/2信号通路；(3)发现GM-CSF通过激活Lyn调控的信号通路增加鼻咽癌的放疗抵抗性，揭示了GM-CSF增强鼻咽癌放疗抵抗的分子机制；(4)发现血清和癌组织GM-CSF水平与放鼻咽癌患者放疗抵抗正相关，而与鼻咽癌患者预后负相关。研究结果表明， GM-CSF过激活Lyn调控的信号通路增加鼻咽癌的放疗抵抗性， GM-CSF有望成为预测鼻咽癌放疗敏感性的标志物，Lyn小分子抑制剂Bafetinib有望用于鼻咽癌的放疗增敏治疗。通过项目研究，发表标注本项目资助的SCI论文7篇。