Niu Hao, Zhu Yi, Wang Jie, Wang Tian, Wang Xiaosheng, Yan Li
Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China.
Department of Radiation Oncology, Eye and ENT Hospital, Fudan University, Shanghai, China.
Transl Oncol. 2022 Aug;22:101466. doi: 10.1016/j.tranon.2022.101466. Epub 2022 Jun 10.
The relationship between ubiquitin specific protease 7 (USP7) and radio-sensitivity in laryngeal squamous cell carcinoma (LSCC) has not been reported yet. Using gene chip and Label-Free mass spectrometry, we found that USP7 was significantly increased both in radioresistant LSCC patients and LSCC cells receiving irradiation. Since p53 is the most important downstream gene of USP7 and is frequently mutated in LSCC, we investigated the effects of USP7 on radioresistance of LSCC cells with or without p53 mutation. We found that knockdown of USP7 increased the radio-sensitivity in p53-mutated LSCC cells, while inhibiting the radio-sensitivity in p53-wild type cells. Knockdown of USP7 significantly inhibited the expression of the p53 and p53 pathway. Overexpressing endogenous p53 by CRISPR/dCas9 could reverse the effects of USP7 on radiosensitivity both in vitro and in vivo. Our results demonstrated the irradiation-induced USP7 led to radioresistance in p53-mutated LSCC cells but radio-sensitivity in p53-wild type cells. Therefore, the clinical application of USP7 inhibitors may improve the effects of radiotherapy in LSCC with p53 mutations and reduce the side effects on surrounding normal tissues without p53 mutation.
泛素特异性蛋白酶7（USP7）与喉鳞状细胞癌（LSCC）放射敏感性之间的关系尚未见报道。通过基因芯片和无标记质谱分析，我们发现USP7在放射抗性LSCC患者和接受照射的LSCC细胞中均显著升高。由于p53是USP7最重要的下游基因且在LSCC中经常发生突变，我们研究了USP7对有或无p53突变的LSCC细胞放射抗性的影响。我们发现，敲低USP7可增加p53突变的LSCC细胞的放射敏感性，同时抑制p53野生型细胞的放射敏感性。敲低USP7显著抑制p53及p53通路的表达。通过CRISPR/dCas9过表达内源性p53可在体外和体内逆转USP7对放射敏感性的影响。我们的结果表明，辐射诱导的USP7导致p53突变的LSCC细胞产生放射抗性，但使p53野生型细胞产生放射敏感性。因此，USP7抑制剂的临床应用可能会提高对p53突变的LSCC放疗效果，并减少对周围无p53突变正常组织的副作用。
