MEMO1调控IGF-IR介导HER2阴性胃癌转移的机制研究

抗HER2靶向治疗可以在化疗基础上显著提高晚期胃癌的疗效，但胃癌的低HER2扩增率限制其临床应用。胰岛素样生长因子-I受体（IGF-IR）是在胃癌组织中广泛表达且影响预后的受体酪氨酸激酶。本项目前期研究证实：IGF-IR可以介导胃癌细胞转移，且其表达水平与HER2呈负相关；促转移因子MEMO1能够结合IGF-IR和Src激酶；沉默MEMO1或抑制Src通路可以逆转胃癌细胞上皮间质转化。因此，IGF-IR可能是介导HER2阴性胃癌转移的关键因子并有望成为其潜在治疗靶点。本项目提出MEMO1可能通过调控IGF-IR通路介导HER2阴性胃癌转移的假说，拟建立IGF-IR沉默的细胞和动物模型，联合临床标本，研究MEMO1和Src是否通过结合IGF-IR的特异性功能结构域，反馈性激活IGF-IR通路，促进HER2阴性胃癌转移。其结果将为揭示HER2阴性胃癌转移机制和潜在药物治疗靶点提供理论依据。

The addition of HER2-targeted therapy to chemotherapy has improved outcomes for patients with HER2-positive advanced gastric cancer in clinical practice. However, low HER2 amplification rate limits the clinical application of anti-HER2 therapy severely. Insulin-like growth factor-I receptor (IGF-IR) is a receptor tyrosine kinase which is widely expressed and associated with prognosis in gastric cancer. Our original study has demonstrated that: IGF-IR mediates the invasiveness of gastric cancer cells; IGF-IR expression is negatively correlated with HER2 expression in gastric cancer cells; MEMO1(mediator of driven cell motility1) combines with IGF-IR and Src kinase in gastric cancer cells; Knockdown of MEMO1 or inhibition of Src kinase reverse epithelial-mesenchymal transition in gastric cancer cells. Thus, IGF-IR may mediate HER2-negative gastric cancer metastasis and is expected to be a potential therapeutic target. We speculate that MEMO1 plays an important role in HER2-negative gastric cancer metastasis through regulation of IGF-IR signaling pathway. In this study, we will establish stable IGF-IR knockdown cells and animal model to implicate whether MEMO1 and Src kinase combine in specific structural domain of IGF-IR and mediate feedback activation of IGF-IR signaling pathway in inducing HER2-negative gastric cancer metastasis with clinical specimens analysis. The results of this study may be helpful in understanding the molecular mechanism of HER2-negative gastric cancer metastasis and providing scientific basis on new therapeutic target for advanced gastric cancer treatment strategies.