Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science, Tianjin 300192, China.
Radiat Res. 2012 Jan;177(1):52-8. doi: 10.1667/rr2679.1. Epub 2011 Nov 11.
SKP2 is the substrate recognition subunit of the SCF(SKP2) ubiquitin ligase complex. It is implicated in ubiquitin-mediated degradation of the cyclin-dependent kinase (CDK) inhibitor p27(KIP1) and positively regulates the G(1)/S transition. Overexpression of SKP2 has been found in many kinds of tumors. In the present study, we found that SKP2 expression levels increased in esophageal squamous cell carcinoma tissues. Elevated expression of SKP2 correlated significantly with tumor stage and positive lymph node metastasis (P < 0.05). Moreover, a significantly negative correlation was found between SKP2 expression and the survival of patients who received radiotherapy (P < 0.05). At the molecular level, induced expression of SKP2 promoted the radioresistance of EC9706 cells. Knockdown of SKP2 expression sensitized cancer cells to radiation, and a wobble mutant of SKP2 that was resistant to SKP2 siRNA was able to rescue this effect. Increased or decreased expression levels of SKP2 had effects on Rad51 expression after irradiation. These results demonstrate for the first time that overexpression of SKP2 was correlated with the increased radioresistance of esophageal squamous cell carcinoma. Elevated expression of SKP2 promoted the radioresistance of cancer cells, and this effect was mediated at least in part by the Rad51 pathway.
SKP2 是 SCF(SKP2)泛素连接酶复合物的底物识别亚基。它参与细胞周期蛋白依赖性激酶 (CDK) 抑制剂 p27(KIP1) 的泛素介导降解，并正向调节 G1/S 期转换。SKP2 的过表达已在许多类型的肿瘤中发现。在本研究中，我们发现 SKP2 的表达水平在食管鳞状细胞癌组织中升高。SKP2 的高表达与肿瘤分期和阳性淋巴结转移显著相关（P<0.05）。此外，还发现 SKP2 表达与接受放疗的患者的生存呈显著负相关（P<0.05）。在分子水平上，SKP2 的诱导表达促进了 EC9706 细胞的放射抵抗性。SKP2 表达的敲低使癌细胞对辐射敏感，并且对 SKP2 siRNA 具有抗性的 SKP2 摇摆突变体能够挽救这种效应。照射后 SKP2 表达水平的增加或减少对 Rad51 表达有影响。这些结果首次证明 SKP2 的过表达与食管鳞状细胞癌放射抵抗性的增加有关。SKP2 的高表达促进了癌细胞的放射抵抗性，这种效应至少部分是通过 Rad51 途径介导的。
