MEMO1调控IGF-IR介导HER2阴性胃癌转移的机制研究

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.

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。

本研究首次探索了MEMO1调控IGF-IR介导HER2阴性胃癌侵袭转移的机制。1.证实IGF-IR通过诱导胃癌EMT发生，介导胃癌侵袭转移，其高表达提示胃癌预后不良；2. 明确了IGF-IR/MEMO1/Src复合物的形成促进胃癌侵袭转移，MEMO1低表达组胃癌患者预后明显优于MEMO1高表达组。此外，本研究首次证实细胞表面波形蛋白CSV是胃癌EMT的重要标志物，可以联合上皮表面标志物EpCAM共同检测晚期胃癌患者外周血循环肿瘤细胞CTCs数量，并具有相对较高的敏感性。IGF-I诱导的CSV表达上调是诱导胃癌细胞侵袭转移的关键。本研究基本按标书计划执行，并在研究中发现了相关研究领域的新结果。已发表课题相关第一作者SCI论文3篇，其它课题相关SCI论文1篇，待发表2篇。本项目在研期间明确了IGF-IR通过诱导胃癌EMT发生，介导胃癌侵袭转移的具体机制，包括IGF-IR/MEMO1/Src复合物的形成，诱导细胞表面CSV表达上调等关键机制。更重要的是，本课题优化了经冻存血液提取CTCs的技术瓶颈，证实CSV是检测EMT-CTCs的特异性细胞表面标记物，为临床液态活检的广泛开展尤其是针对晚期胃癌病人精准分离和筛选CTCs细胞提供了新的思路和理论依据。