分子伴侣介导的自噬通过清除过度氧化的DJ-1促进胃癌细胞的抗氧化应激能力

Although numerous studies have reported the close involvement of macroautophagy in tumor development and progression, Less study has investigated the function of chaperone-mediated autophagy (CMA) in tumor cells. It has been reported that CMA activities are augmented in lung cancer and breast cancer tissues, and participate in regulating proliferation and survival of tumor cells, but the molecular mechanisms are elusive. Our previous study has proved that, LMAP2A, the rate limiting and receptor molecule of CMA, is overexpressed in 8 kinds of frequent tumors, indicating that CMA is universally activated in solid tumors；Further study has proved that CMA can maintain the rapid proliferation of gastric cancer cells via degrading RND3, meanwhile, we have also found that CMA may also able to degrade the antioxidant protein DJ-1(Autophagy，2016). Another study has suggested that, mild oxidation of DJ-1 protein can sustain the viability of tumor cells, whereas excessive oxidation of this protein triggers cell apoptosis. Thus, we conjecture that CMA can favor the antioxidative ability and survival of GC cells by degrading excessively oxidized DJ-1. This study aims to validate our hypothesis and thus to illustrate the function and underlying mechanism of CMA in combating oxidant stress.

尽管大量研究证实大自噬与肿瘤的发生发展密切相关，但分子伴侣介导的自噬（CMA）在肿瘤细胞中的作用却鲜有报道。研究表明CMA在肺癌和乳腺癌细胞中活性增强并参与细胞的增殖和生存，但分子机制并不明确。我们前期研究证明，CMA的限速及受体分子LAMP2A在八种常见的实体瘤组织中表达增多，表明CMA在肿瘤组织中普遍被激活；进一步发现CMA通过降解RND3而维持胃癌细胞的快速增殖，同时我们还发现抗氧化蛋白DJ-1也可能通过 CMA途径进行降解（Autophagy，2016）。另有研究发现，DJ-1轻度氧化时有利于肿瘤细胞的生存，而其过度氧化时反而促进肿瘤细胞发生凋亡。因此我们推测CMA可能通过选择性地清除过度氧化的DJ-1而防止肿瘤细胞发生凋亡。本研究拟在胃癌细胞中验证该假设，从而阐明CMA在调节肿瘤细胞抗氧化应激中的作用及分子机制。