EGFR高表达的食管鳞状细胞癌放疗获益的分子机制研究

In 2003, we first demonstrated that postoperative radiotherapy could benefit 31% of the patients of esophageal squamous cell carcinoma with positive lymph node metastasis or 35% of them with stage III. In order to identify the subset of patients who could benefit from postoperative radiotherapy before the treatment, we applied a multi-gene test using random pathologic samples in 411 cases who had been diagnosed as esophageal squamous cell carcinoma and underwent postoperative radiotherapy. We concluded in the first time that the patients of esophageal squamous cell carcinoma with EGFR high expression could benefit from postoperative radiotherapy, while the ones with EGFR low expression will not. This conclusion is in accord with the theory of "oncogene addiction", that is, the malignant phenotype of the cancer cells with EGFR high expression depends on the expression of EGFR, interruption of this dependent factor by radiotherapy will be helpful for those patients. Based on our privious data, this subject aims to study the changes of protein expression level and intracellular location of EGFR before and after radiographic exposure being implemented, the alteration of expression and activity of the response signal molecules involved in the EGFR signal transduction pathway, and therefore elucidate the potential molecular mechanism that the patients of esophageal squamous cell carcinoma with EGFR high expression can benefit from radiotherapy. Hopefully, our research could provide theoretical guidance for future clinical practice.

2003年，我们在国际上首先发现术后放疗能使31％LN+和35％Ⅲ期的食管鳞癌患者获益。为了在治疗前识别、筛选和确定术后放射治疗获益的特定食管鳞癌患者，在2011年完成441例食管鳞癌术后放疗随机病理标本的多个基因检测，在国际上首次提出EGFR高表达的食管鳞癌患者能从术后放疗中获益，而低表达患者则不获益。这一结论符合"癌基因成瘾"理论，即EGFR高表达细胞的恶性表型依赖于EGFR的表达，而放疗很可能阻断或者去除了这一依赖因素，从而使得这部分患者从放射治疗中获益。本课题将围绕这一原创临床研究结果，从分子水平探讨和研究EGFR高表达的食管鳞癌患者如何从放疗中获益的机制，研究放射线照射前后EGFR蛋白表达及细胞内定位的变化、EGFR通路重要信号分子表达及活性变化。从而，丰富和拓展对于放射线照射在食管鳞癌组织中作用于EGFR信号通路分子机制的认识；同时，具有为临床提供理论指导的应用价值。

我们前期在国际上首先发现术后放疗能使31％LN+和35％Ⅲ期的食管鳞癌患者获益。为了在治疗前识别、筛选和确定术后放射治疗获益的特定食管鳞癌患者，本研究检测了食管鳞癌EGFR蛋白表达，并且分析EGFR表达与患者放疗效果的相关性，结果提示EGFR高表达患者预后较差但是放疗可使其获益；在细胞水平利用放射线照射细胞，检测了EGFR在细胞内定位改变及相关信号蛋白的改变，结果提示放射治疗可以直接影响EGFR 信号通路，进而抑制食管癌细胞生长; EGFR靶向抗体西妥昔与放射治疗对于EGFR信号通路的影响不同,而且放疗联合EGFR靶向治疗对EGFR信号通路抑制更明显，细胞抑制效果更强。此外，EGFR信号通路可以调控食管癌细胞PD-L1的表达，影响食管癌的发展和治疗效果。本研究从细胞和分子水平探讨了EGFR信号通路对于食管癌放疗疗效的影响及作用机制，为EGFR用于临床预后预测及靶向治疗提供了理论依据。