MnSOD在食管鳞癌发生中的作用及双向调节食管癌放疗敏感性的分子机制研究

MnSOD is an important antioxidant enzyme in cells. Expression of MnSOD in esophageal squamous cancer tissues is significantly lower than that in normal tissues. Esophageal squamous cell carcinoma tissues were methylated in all the fifteen cases, while normal esophageal tissues was not methylated in MassARRAY analysis, indicating that loss of MnSOD was the pathogenesis of esophageal cancer, and hypermethylation was the mechanism. Further study revealed that colony forming ability decreased in esophageal cancer cells overexpressing moderate MnSOD overexpression and radiation sensitivity was significantly improved, while high overexpression of MnSOD increased colony forming ability and reduced radiation sensitivity. Immunofluorescence confirmed that the number of γH2AX foci in esophageal carcinoma cells expressing moderate MnSOD overexpression was greater than that in esophageal carcinoma cells expressing high MnSOD overexpression after 2 Gy radiation treatment. This indicated that MnSOD showed bidirectional regulation in regards to the radiosensitivity of esophageal carcinoma cells, possibly by regulation of DNA damage repair genes. However, the mechanism and key target protein remain unknown. This study helps define the role of MnSOD in the pathogenesis of esophageal squamous cancer and the mechanism of bidirectional regulation on the radiosensitivity of esophageal squamous cancer cells.

MnSOD是细胞中一种重要的抗氧化酶。前期研究证实食管鳞癌组织中MnSOD 表达水平较正常食管组织明显降低。MassArray甲基化检测发现15例食管鳞癌组织全部发生甲基化，而在15例正常食管组织中无一例甲基化。推测MnSOD高甲基化是其在食管癌中沉默的主要机制。进一步研究发现中等过量表达MnSOD的食管癌细胞集落形成能力降低，放射敏感性显著提高；而高过量表达MnSOD时作用则与之相反。免疫荧光证实2Gy放射线照射后，中等过量表达MnSOD的食管癌细胞中γH2AX焦点数较高过量表达MnSOD时明显增多；提示不同过量表达的MnSOD可能通过调控DNA损伤修复相关基因的表达来实现对食管癌细胞放疗敏感性的双向调节。但是不同过量表达的MnSOD是通过什么相互作用的蛋白在食管癌放疗敏感性的双向调节中起作用？这些存在问题的阐明将有助于明确MnSOD在食管癌发生中的作用及双向调节其放疗敏感性的分子机制。