USP22调控EGFR内吞作用介导肺腺癌的EGFR-TKIs耐药

EGFR-TKIs have been the first choice in EGFR mutation patients of advanced lung adenocarcinoma. Unfortunately, drug resistance is inevitable in almost all of the patients eventually. The study found that EGFR-TKIs resistance was closely related to endocytosis mediated EGFR activation by the regulation of ubiquitination. We revealed that cancer cells manifesting USP22 showed a strong tendency to metastasis and inhibited ubiquitination of EGFR. Furthermore the high expression of USP22 correlated with the EGFR-TKIs resistance in lung adenocarcinoma patients and affected the sensitivity in EGFR-TKIs resistance cells. Thus, we proposed that USP22 antagonizes EGFR endocytosis via deubiquitination of EGFR and thus amplifies EGFR signaling activity from the receptor to promote EGFR-TKIs resistance in lung adenocarcinoma. To test this hypothesis, in cell, animal and tissue, we are aiming to explore the role of USP22 in EGFR-TKIs resistance of lung adenocarcinoma, and elucidate the pivotal role of USP22 deubiquitination modification in aspect of EGFR endocytosis. We will provide new target and new idea for exploring the mechanism of EGFR-TKIs resistance from the new perspective of deubiquitination modification.

EGFR-TKIs已经成为EGFR突变型晚期肺腺癌患者的首选用药。然而遗憾的是，几乎所有患者最终都不可避免发生耐药。研究发现EGFR-TKIs耐药与EGFR内吞转运作用的异常密切相关，并且受泛素化修饰的调控。我们发现去泛素酶USP22标记的癌细胞具有强烈的转移倾向，能够抑制EGFR的泛素化；同时USP22的高表达与肺腺癌患者EGFR-TKIs耐药正相关，并且影响EGFR-TKIs耐药细胞的药物敏感性。所以我们提出假设：USP22通过去泛素化修饰调控EGFR的内吞转运作用并激活EGFR信号传导通路促进肺腺癌的EGFR-TKIs耐药。为此我们从细胞、裸鼠及人体组织标本等方面探讨USP22在肺腺癌EGFR-TKIs耐药中的作用；明确USP22的去泛素化修饰在EGFR的内吞转运作用中的核心调控作用。本研究将从去泛素化修饰的新视点为揭示肺腺癌EGFR-TKIs的耐药机制提供新靶点和新思路。

一、背景：.EGFR-TKIs（表皮生长因子受体酪氨酸激酶抑制剂）已经成为EGFR突变型晚期肺腺癌患者的首选用药。然而遗憾的是，几乎所有患者最终都不可避免发生耐药。研究发现EGFR-TKIs耐药与EGFR内吞转运作用的异常密切相关，并且受泛素化修饰的调控。所以我们提出假设：USP22通过去泛素化修饰调控EGFR的内吞转运作用并激活EGFR信号传导通路促进肺腺癌的EGFR-TKIs耐药。.二、主要研究内容：.我们通过人非小细胞肺癌细胞系、人肺癌组织和裸鼠接种模型，采用基因干扰、基因过表达、Real-time PCR、Western blot、免疫荧光、免疫共沉淀等手段，从分子、细胞、组织、及动物整体水平等多方面探讨USP22在肺腺癌EGFR-TKIs耐药中的作用；明确USP22的去泛素化修饰在EGFR的内吞转运作用中的核心调控作用。.三、重要结果：.1）在SCI收录杂志上发表的课题相关学术论文。.2）USP22与肺腺癌 的EGFR-TKIs耐药相关。.3）USP22通过去泛素化修饰调控细胞内EGFR的内吞转运作用，进而导致EGFR依赖的信号通路过度活化。.4）调节USP22的功能可以有效逆转肺腺癌的EGFR-TKIs耐药。.5）在EGFR突变的肺腺癌中金诺芬能够增强依鲁替尼的抗肿瘤活性。.6）培养1名博士后，3名博士及2名硕士研究生，并积极参加与课题相关的学术交流会议。.四、关键数据：.1）USP22对EGFR-TKIs相关肺腺癌细胞系生物学行为的影响。.2）USP22对EGFR以及EGFR信号通路的影响。.3）USP22 通过去泛素化修饰调控EGFR 的内吞转运作用介导肺腺癌EGFR-TKIs的耐药。.4）体内裸鼠实验验证USP22促进肺腺癌EGFR-TKIs耐药的发生。.5）人体组织标本中检测USP22的表达与EGFR-TKIs治疗耐药相关。.五、科学意义：.本研究将从去泛素化修饰的新视点为揭示肺腺癌EGFR-TKIs的耐药机制提供新靶点和新思路，为临床患者的个体化治疗提供新的思路。