HIF-1α/BCL2信号对12C离子治疗晚期非小细胞肺癌的调控作用研究

Statistical data have revealed that, in the early stage of non-small cell lung cancer (NSCLC), the patients with carbon ions treatment have higher 5-years survival rate compared to those with tradiational radiotherapy. Up to now, the clinical and experimental data have rarely shown carbon beam radiotherapy was used in advanced stage of NSCLC, although there are 2/3 patients with NSCLC in advanced stage. On the other hand, according to previous reports, intracellular HIF-1α/BCL-2 signal was closely related with the clinical stage, progression, curative effect and prognosis of tumor. In this study, NSCLC cells with high-expression of HIF-1α, which were established in our previous experiment, will be used to investigate survival of NSCLC cells exposed to carbon ions irradiation by HIF-1α/BCL-2 signal in vitro and in vivo. In vivo experiment, animal models with advanced stages of NSCLC will be further established. Subsequently, the changes of the tumor inhibition rate, survival time, status of metastasis and life-quality of animals with advanced NSCLC by HIF-1α and BCL-2 inhibitors preliminary injection will be observed after carbon ions irradiation. The alteration of peripheral blood and myelosuppression will be monitored at the same time. In short, the efficiency of carbon beam irradiation on advanced NSCLC and the role of HIF-1α/BCL-2 signal regulating may be researched and evaluated by this study.

12C离子已被用于早期非小细胞肺癌(NSCLC) 治疗，病人的5年生存率显著高于常规放疗。然而，对于NSCLC发现时已处于中晚期的2/3病人，目前尚缺乏12C离子辐射治疗研究的基础和临床数据。HIF-1α/BCL-2信号被报道与肿瘤的分期和预后关系密切，本课题组利用前期已建立的高表达HIF-1α的NSCLC细胞，进行离体和活体实验，通过对HIF-1α/BCL-2信号通路的调控，研究其对12C离子照射后NSCLC细胞存活的影响。在此基础上，采用晚期NSCLC动物模型，经HIF-1α/BCL-2信号抑制剂预处理后，通过抑瘤率、生存时间、转移情况、生活质量指标，以及外周血变化和骨髓抑制情况，评价和研究12C离子对晚期NSCLC的疗效以及HIF-1α/BCL-2信号的调控作用。

2/3的非小细胞肺癌(NSCLC)患者在发现时已属中晚期，如何提高晚期NSCLC的放疗效果具有非常重要的临床意义。HIF-1α被报道与肿瘤的分期和愈后关系密切，本项目利用前期构建的2种高表达HIF-1α的人NSCLC细胞，深入研究了HIF-1α/BCL-2信号通路在受照射的NSCLC细胞和晚期肺癌荷瘤动物模型中的表达变化，以及HIF-1α/BCL-2信号变化对NSCLC细胞放射敏感性和晚期肺癌动物生存的影响，同时，观察了高LET射线(12C重离子射线)对HIF-1α/BCL-2信号通路的影响。实验结果显示，低LET射线(X射线)能够在常氧情况下激活HIF-1α/BCL-2信号，从而降低NSCLC细胞的放射敏感性，反之，抑制HIF-1α/BCL-2信号可有效增强X射线对NSCLC细胞的杀伤效应并有效提高晚期肺癌动物的生存时间，而12C重离子射线对HIF-1α/BCL-2信号不具有活化作用，可能有效抑制NSCLC细胞的生长。因此，HIF-1α/BCL-2信号通路是晚期NSCLC常规放疗增敏的重要靶点，12C重离子射线的阻断作用是其有效抑制NSCLC细胞生长的重要机制之一。