抑制细胞自噬活性增强食管鳞状细胞癌放射治疗敏感性研究

Radiotherapy is an important effective therapeutic approach for esophageal squamous cell carcinoma, however, residual or recurrent tumor due to radio-resistance is the main reason of treatment failure. Autophagy, hallmarked by the formation of double-membrane bound organelles known as autophagosomes, is a lysosome-dependent pathway for cytosolic proteins and organelles degradation. Our preliminary study showed that radiation activated the process of autophagy and inhibition of this process increased the effect of radiation for killing esophageal squamous carcinoma cells, we thus speculated that autophagy acted as a role in protecting esophageal squamous carcinoma cells form radiation-induced cellular damage. The aim of this study is to investigate the related mechanisms of radiosensitivity in ESCC through autophagy inhibition. The treatment modalities including autophagy inhibition, radiation alone and radiation combined with autophagy inhibition are used to assess whether the inhibition of autophagy can enhance radiation sensitization in esophageal squamous carcinoma cells. Cell apoptosis, cell cycles distribution, autophagy-related genes, cancer cell invasion and metastasis are analyzed in vivo and in vitro. Tissue specimens form the ESCC patients receiving radiotherapy will also be collected to evaluate the correlation of Beclin-1、LC3 expressions and radiosensitivity and prognosis in the patients. An important clinical strategy for judging the efficacy of radiotherapy and guiding individual treatment choices of ESCC can be possibly decided from the results of this study.

放射治疗是食管鳞状细胞癌 (ESCC) 最重要的治疗手段之一，而由于放射抗拒所致的肿瘤局部未控或复发成为治疗失败的主要原因。自噬是溶酶体介导的细胞内蛋白或细胞器的降解途径。我们前期研究发现放疗诱导 ESCC 细胞内自噬增加，而抑制自噬活性增加了放疗对肿瘤细胞的杀灭效应，因此推测自噬可保护 ESCC 细胞免受治疗的损伤。本研究一方面探讨通过抑制细胞自噬活性来增强 ESCC 放疗敏感性的机制：选择单纯自噬抑制、单纯放疗和放疗联合自噬抑制的方式，利用体外实验和裸鼠动物模型，分析细胞凋亡、细胞周期分布的变化、自噬相关因子的调节和癌细胞的侵袭转移，论证自噬抑制可否促进 ESCC 的放射治疗效果；另一方面收集接受放疗前 ESCC 患者的组织标本，研究自噬相关因子 Beclin-1、LC3 的表达与放疗敏感性和预后的关系。该研究可能为评判 ESCC 放疗效果和个体化治疗提供重要的临床策略。

放射治疗是食管鳞状细胞癌 (ESCC) 最重要的治疗手段之一，但局部未控或复发是放疗失败的主要原因。自噬是溶酶体介导的细胞内蛋白或细胞器的降解途径，国内外对自噬在肿瘤治疗中的作用研究很重视。我们对细胞自噬效应在影响食管鳞癌的生长增殖和放疗敏感性的问题进行了深入探讨。首先，体外和动物体内实验发现，抑制细胞自噬活性可使ESCC细胞增殖和集落生成减少，增加放疗敏感性1.76倍；联合放疗使裸鼠移植瘤体积快速缩小，同时抑制了肿瘤新生血管的产生。然后，我们收集了150例接受根治性同步放化疗的II-IVA期ESCC患者标本，检测了自噬相关因子 Beclin-1和LC3在治疗前的表达情况，发现Beclin-1和LC3 低表达者有较高的放疗敏感性和较好的预后 (P = 0.038)。多因素分析显示病变期别 (P = 0.019)，治疗反应 (P = 0.002) 和LC3 (P = 0.021) 表达水平是预后的独立影响因子。该研究通过体外---动物---患者标本的一系列探讨，获得了重要的研究成果，发现细胞自噬活性的改变影响ESCC放疗敏感性，为ESCC放疗效果的评判和个体化治疗提供重要的临床策略。