USP11去泛素化调控Nrf2/ARE通路对食管癌放射敏感性的影响及机制研究

Esophageal cancer is one of the deadliest malignancies worldwide and in China. Radiosensitivity of esophageal cancer cells affects radiation efficacy and prognosis. Tumor cells have envolved multiple to defense reactive oxygen species induced by irradiation. Nrf2/ARE is the most important system to counteract the radiation-induced ROS. USP11 Ubiquitin specific protease 11 (USP11) is an important enzyme in the deubiquitination family. We have found that USP11 is overexpressed in esophageal cancer tissues and that USP11 could stabilize Nrf2. Moreover, knock-down of USP11 increased the radiosensitivity of esophageal cancer cells. However, this radiosensitizing mechanism remains unclear. This project will use mutiple molecular biology methods to illustrate the following issues: 1) the process how radiation induces USP11 and Nrf2 expression and cellular distribution; 2) how USP11 regulates the expression of Nrf2; 3) effects and mechanism of USP11 on radiosensitivity. Moreover, this project will construct a USP11-targeting lentivirus to enhance radiosensitivity of esophageal cancer cells. This project aims to illustrate the mechanism of induced radiosensitivity by USP11 and provides new methods to increase radiosensitivity of esophageal cancer cells.

我国是食管癌高发国家，提高食管癌的放射敏感性对增加食管癌放疗疗效具有重要意义。肿瘤细胞在应对电离辐射等引起活性氧自由基损害时形成了一套复杂的氧化应激系统，其中Nrf2/ARE 通路是迄今为止发现的最为重要的内源性抗氧化应激通路。泛素特异性蛋白酶11(USP11)是去泛素化酶家族中的重要一员。我们前期研究表明泛素化酶USP11在食管癌中高表达并能去泛素化稳定Nrf2；敲低USP11可显著增加食管癌细胞的放射敏感性，但具体机制及功能不详。本项目拟通过多种分子生物学方法揭示放射线对USP11和Nrf2表达及核定位的影响；阐明USP11可去泛素化并稳定Nrf2从而引起食管癌放射抵抗的机理；同时在细胞水平和动物水平通过靶向USP11的重组慢病毒抑制USP11的表达水平，实现食管癌放射增敏。本项目有望从USP11-Nrf2/ARE通路的角度揭示食管癌放射抗拒的机理，为食管癌放射增敏提供理论依据和方法。

提高食管癌的放射敏感性对增加食管癌放疗疗效具有重要意义。肿瘤细胞在应对电离辐射等引起活性氧自由基损害时形成了一套复杂的氧化应激系统，其中Nrf2/ARE 通路是迄今为止发现的最为重要的内源性抗氧化应激通路。泛素特异性蛋白酶11(USP11)是去泛素化酶家族中的重要一员。我们通过免疫组化发现去泛素化酶USP11在食管癌中高表达，敲低USP11后能抑制两种食管癌细胞的生长、增殖、迁移并增加其对电离辐射的敏感性。我们进一步在动物实验上证实了USP11对食管癌的促进作用。我们进一步通过Co-IP等手段发现USP11可去泛素化并稳定Nrf2，从而增加食管癌细胞对电离辐射的抗拒性。本项目从USP11-Nrf2/ARE通路的角度揭示食管癌放射抗拒的机理，为食管癌放射增敏提供了新的理论依据和方法。. 本项目发表国内核心期刊论文及SCI论文共14篇，其中包括Oncogene等著名杂志。 申请发明专利2项，获授权专利1项。 协助培养硕士研究生2名。项目负责人获常州市科技进步三等奖一项。