IGF1信号通路在某些表现出生存率低和化疗抗性类型的胃癌(GC)亚型中高度激活。虽然抗IGF1R单克隆抗体和IGF-1R抑制剂的临床试验结果在未选择的癌症患者中大多令人失望，但在这些失败的研究中，一些患者从抗IGF1R治疗中受益。因此，有必要对GC中复杂的IGF信号通路进行表征并帮助完善针对IGF1通路的策略。我们发现GC细胞系对特异性IGF1R抑制剂OSI906呈现差异性反应。根据OSI906处理后Akt的磷酸化状态，我们将GC细胞系分为IGF1R依赖和IGF1R非依赖细胞。体外和体内实验均表明，通过Dox诱导的NEDD4敲down明显抑制IGF1R依赖型GC细胞的肿瘤生长，而NEDD4过表达则促进IGF1R依赖型GC细胞的肿瘤生长。相反，NEDD4沉默和过表达都不影响IGF1R非依赖型GC细胞的增殖。拯救实验表明，PTEN-IRS1轴是NEDD4介导的Akt激活和GC细胞肿瘤生长调节所必需的。临床上，与IGF1低的GC组织和正常组织相比，NEDD4在IGF1高的GC组织中表达更高，并且NEDD4和IGF1的共高表达预示着GC患者预后较差。综上所述，我们的研究证明，NEDD4通过拮抗PTEN对IRS1的蛋白磷酸酶活性，特异地促进依赖IGF1/IGF1R信号通路的GC细胞增殖，并且靶向NEDD4可能是治疗IGF1信号通路驱动的胃癌的有前途的策略。©2023. 作者。

The IGF1 signal pathway is highly activated in some subtype of gastric cancer(GC) that exhibits poor survival and chemotherapy resistance. Although the results of clinical trials of anti-IGF1R monoclonal antibodies and IGF-1R inhibitors have been mostly disappointing in unselected cancer patients, some patients benefit from anti-IGF1R therapy in these failed studies. Therefore, it is necessary to characterize the complex IGF signaling in GC and help refine the strategies targeting the IGF1 pathway. We found that GC cell lines exhibit differential responses to the specific IGF1R inhibitor OSI906. According to the phosphorylation status of Akt upon the OSI906 treatment, we divided the GC cell lines into IGF1R-dependent and IGF1R-independent cells. Both in vitro and in vivo experiments indicate that Dox-induced knockdown of NEDD4 significantly suppresses tumor growth of IGF1R-dependent GC cells and NEDD4 overexpression promotes tumor growth of IGF1R-dependent GC cells. In contrast, the proliferation of IGF1R-independent GC cells is not affected by NEDD4 silencing and overexpression. The rescue experiments show that a PTEN-IRS1 axis is required for NEDD4-mediated regulation of Akt activation and tumor growth in GC cells. Clinically, NEDD4 is expressed higher in IGF1-high GC tissues compared with IGF1-low GC tissues and normal tissues, and the co-high expression of NEDD4 and IGF1 predicts a worse prognosis in GC patients. Taken together, our study demonstrated that NEDD4 specifically promotes proliferation of GC cells dependent on IGF1/IGF1R signaling by antagonizing the protein phosphatase activity of PTEN to IRS1, and targeting NEDD4 may be a promising therapeutic strategy for IGF1 signal pathway-driven gastric cancer.© 2023. The Author(s).