Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
Cell Death Dis. 2018 Aug 30;9(9):887. doi: 10.1038/s41419-018-0895-0.
Radiation therapy is an important treatment modality for esophageal cancer. However, acquisition of radioresistance ultimately results in esophageal cancer relapse. CD59, a membrane-bound complement regulatory protein, can transduce signals via a Src kinase in the lipid raft, thus playing a complement-independent role. However, the effect of CD59 on the esophageal cancer response to ionizing radiation remains unclear. In this study, we found that the expression level of CD59 was positively correlated with the radioresistance of esophageal cancer cell lines and clinical specimens. High CD59 expression indicated poor overall survival (OS) and disease-free survival (DFS) in esophageal squamous cell carcinoma (ESCC) patients who received radiotherapy. Genetic alteration of CD59 expression modulated the radiosensitivity of esophageal cancer cells to ionizing radiation. CD59 deficiency exacerbated DNA damage, hindered cell proliferation, and induced G2/M cell cycle arrest and cellular senescence, leading to an impaired DNA damage repair ability. In addition, CD59 deficiency almost completely reduced the phosphorylation of Src at Y416 despite ionizing radiation. A Src inhibitor saracatinib sensitized esophageal cancer cells to irradiation. Therefore, CD59 may be a potential biomarker for predicting the radioresistance of ESCC to radiotherapy.
放射治疗是食管癌的重要治疗方法。然而，获得放射抗性最终导致食管癌复发。CD59 是一种膜结合的补体调节蛋白，可通过脂质筏中的Src 激酶转导信号，从而发挥补体非依赖性作用。然而，CD59 对食管癌对电离辐射的反应的影响尚不清楚。在这项研究中，我们发现 CD59 的表达水平与食管癌细胞系和临床标本的放射抗性呈正相关。高 CD59 表达表明接受放射治疗的食管鳞状细胞癌（ESCC）患者的总生存期（OS）和无病生存期（DFS）较差。CD59 表达的遗传改变调节了食管癌细胞对电离辐射的放射敏感性。CD59 缺乏加剧了 DNA 损伤，抑制了细胞增殖，并诱导 G2/M 细胞周期停滞和细胞衰老，导致 DNA 损伤修复能力受损。此外，尽管存在电离辐射，CD59 缺乏几乎完全减少了 Y416 处 Src 的磷酸化。Src 抑制剂 saracatinib 使食管癌细胞对辐射敏感。因此，CD59 可能是预测 ESCC 对放疗的放射抗性的潜在生物标志物。
