靶向A2BR/ZEB1通路抑制肺癌放疗抵抗及转移的机制研究

复发和转移是肺癌放疗失败的主要原因，临床缺少有效干预措施。A2BR作为腺苷受体，调控DNA修复和肿瘤转移，但A2BR是否调控放疗抵抗与放疗后肿瘤转移尚不清楚。本项目前期发现：与单纯放疗相比，shRNA干扰A2BR联合放疗后肺癌细胞的克隆形成力及迁移力降低，荷瘤鼠肿瘤转移灶减少；RNA-seq发现，A2BR阳性肺癌细胞中调控放疗抵抗及转移的ZEB1转录增加。据此推断，A2BR可能通过ZEB1介导肺癌细胞的放疗抵抗与转移。项目通过基因及药物干扰A2BR、ZEB1，验证其是否调控肺癌放疗抵抗和转移，通过Western Blot和抑制剂寻找A2BR/ZEB1下游信号分子，最后利用荷瘤鼠实验验证靶向抑制A2BR联合放疗的疗效。课题以A2BR为靶点，研究靶向阻断A2BR联合放疗增加放疗敏感性、减少放疗后肺癌复发和转移的作用和机制，为肺癌的临床治疗提供新的治疗策略。

Tumor recurrence and metastasis after radiotherapy is the main reason for treatment failure，and the therapeutic means to block them is urgently needed. Adenosine 2B receptor (A2BR) facilitates DNA damage response and metastasis. However，whether A2BR is involved in radioresistance and metastasis after radiotherapy are poorly understood. Previously, we found that A2BR knockdown decreased colony formation ability and migration when lung cancer cells CMT64 was treated with radiotherapy. RNA-seq analysis revealed that transcription of ZEB1, which promotes DNA damage response and radioresistance, was significantly higher in A2BR+ subclone of CMT64 cells. There results suggest that A2BR may cause radioresistance and metastasis after radiotherapy. In our project we will inhibit A2BR expression by shRNA to demonstrate the role of A2BR and ZEB1 in radioresistance and metastasis of lung cancer, and will delineate the underlying molecular mechanisms. We will also use tumor bearing mice to examine whether co-administration of A2BR inhibitor will decrease lung cancer metastasis after radiotherapy. Our project will provide novel scientific insights and provide a therapeutic strategy to enhance radiosensitivity and to inhibit metastasis after radiotherapy, which may improve clinical outcome in lung cancer.