Silencing UHRF1 Enhances Radiosensitivity of Esophageal Squamous Cell Carcinoma by Inhibiting the PI3K/Akt/mTOR Signaling Pathway.
Silencing UHRF1 Enhances Radiosensitivity of Esophageal Squamous Cell Carcinoma by Inhibiting the PI3K/Akt/mTOR Signaling Pathway.
复制标题
沉默 UHRF1 通过抑制 PI3K/Akt/mTOR 信号通路增强食管鳞状细胞癌的放射敏感性
DOI：
10.2147/cmar.s311192
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发表时间：
2021
影响因子：
3.3
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Hui B;Pan S;Che S;Sun Y;Yan Y;Guo J;Gong T;Ren J;Zhang X
目的局部晚期食管鳞状细胞癌（ESCC）对放射治疗抵抗导致治疗失败率高。Ubiquitin-like with plant homeodomain and ring-finger domains 1（UHRF 1）与食管鳞癌预后不良相关。本研究旨在探讨UHRF 1基因沉默对食管鳞癌放射敏感性的影响及其可能机制。方法通过体内外实验观察UHRF 1基因沉默对食管鳞癌放射敏感性的影响。流式细胞仪检测UHRF 1基因沉默对食管鳞癌细胞凋亡的影响。Western blot检测凋亡相关因子caspase-3和Bcl-2、PI 3 K/Akt/mTOR信号通路相关因子PTEN、p-Akt和Akt、p-mTOR和mTOR、DNMT 1的表达，甲基化特异性PCR检测PTEN甲基化状态。采用免疫组化法检测移植瘤组织中PTEN、p-AKT、p-mTOR的表达。结果体内外实验表明，UHRF 1基因敲低可抑制食管鳞癌细胞的生长，增强其放射敏感性。shUHRF 1联合放射治疗可显著增加食管鳞癌细胞凋亡。同时激活caspase-3的表达，抑制Bcl-2的表达。shUHRF 1通过抑制DNMT 1的表达，降低PTEN的甲基化水平，进而上调PTEN的表达，抑制PI 3 K/Akt/mTOR信号通路。相反，PI 3 K/Akt/mTOR信号通路可通过上调UHRF 1而被激活。结论UHRF 1作为靶点提高食管鳞癌的放射敏感性提供了理论依据。
Purpose Resistance to radiotherapy results in a high treatment failure rate for locally advanced esophageal squamous cell carcinoma (ESCC). Ubiquitin-like with plant homeodomain and ring-finger domains 1 (UHRF1), is associated with poor prognosis in ESCC. The present study aims to characterize the effect of UHRF1 silencing on the radiosensitivity of ESCC and its potential mechanism. Methods Both in vitro and in vivo experiments were conducted to observe the effects of UHRF1 silencing on the radiosensitivity of ESCC. The effects of UHRF1 silencing on the apoptosis of ESCC cells were assessed by flow cytometry. The expression of apoptosis-related factors (caspase-3 and Bcl-2), PI3K/Akt/mTOR signaling pathway-related factors (PTEN, p-Akt and Akt, p-mTOR and mTOR), and DNMT1 were measured via Western blot, and the status of PTEN methylation was detected by methylation-specific PCR. Immunohistochemistry was used to detect the expressions of PTEN, p-AKT, and p-mTOR in xenograft tumor tissues. Results In vitro and in vivo experiments showed that UHRF1 knock-down inhibited ESCC cell growth and enhanced their radiosensitivity. shUHRF1 combined with radiation significantly increased ESCC cell apoptosis. Meanwhile, it activated the expression of caspase-3 and inhibited the expression of Bcl-2. shUHRF1 inhibited the expression of DNMT1 and reduced the methylation of PTEN, and then upregulated the expression of PTEN to inhibit the PI3K/Akt/mTOR signaling pathway. On the contrary, the PI3K/Akt/mTOR signaling pathway can be activated by upregulation of UHRF1. Conclusion Our findings provide a theoretical basis for UHRF1 as a target to improve the radiosensitivity of ESCC.