人红细胞阴离子交换蛋白1在胃癌靶向治疗应用中的研究进展

Progression of targeted therapy of anion exchanger 1 for gastric cancer

胃癌位居我国恶性肿瘤死因的第二位。95%以上的胃癌为腺癌,对放疗和化疗都不敏感;已发生转移的胃癌5年生存率仅15%～20%。因此,寻求有效的早期诊断和靶向治疗方法一直是胃癌研究关注的焦点。该课题组在对人红细胞阴离子交换蛋白1(AE1)的研究中发现,AE1除特异表达在红细胞膜外,在胃癌细胞质中具有83%的高频率表达。AE1的异常表达与碱性环境下p65/miR-24负反馈调控失衡相关。胃上皮细胞内缺乏AE1上膜途径导致AE1表达后大量滞留于细胞质中,胞质内的AE1通过几个相互关联的信号通路参与肿瘤的发生发展进程,主要包括:①与肿瘤抑制蛋白p16直接相互作用,扣押后者在胞质而不能入核发挥细胞周期负调控作用;②妨碍另一家族成员AE2正常上膜,加速AE2降解,进一步促进细胞碱化和Wnt/β-catenin通路活化。这一研究成果已被收录在Atlas of Genetics and Cytogenetics in Oncology and Haematology中。明确了AE1是胃癌分子标志物,在此基础上,课题组在细胞及动物水平开展了针对AE1的胃癌靶向治疗研究。结果显示,靶向AE1可以有效抑制胃癌细胞增殖,能够使药物诱发的小鼠胃癌检出率由62%～70%降低到15.8%。AE1蛋白作为胃癌诊断和治疗的靶标具有非常重要的应用价值。

Gastric cancer is the second leading cause of cancer-related death in China. Gastric adenocarcinoma comprises 95% of the total number of gastric malignancies which is often insensitive to chemo- and radiation therapy, and the 5-year survival rate of patients is only 15% - 20% . Therefore, majority of studies have focused on early diagnosis and targeted therapy of gastric cancer. Our studies have found that human anion exchanger 1 （AE1）, an erythrocyte membrane protein, is unexpectedly expressed in the gastric cancer with 83% frequency. Failure in negative feedback regulation between p65 and miR-24 is involved in aberrant expression of AE1. AE1 is accumulated in cytoplasm because the gastric epithelial cells do not have the ability for AEI membrane trafficking. The cytoplasmic AE1 takes part in the gastric carcinogenesis through several signal pathways which communicate with each other： ①AE1 interacts with the tumor suppressor p16 and sequesters it in the cytoplasm, which leads to loss of negative cell cycle regulation. ②AE1 interrupts AE2 to traffick to the plasma membrane, resulting in intracellular alkalization and activation of Wnt/β-catenin pathway in gastric epithelium. The results have been included in Atlas of Genetics and Cytogenetics in Oncology and Haematology. Based on the premise that AE1 is a useful biomarker for gastric cancer, the AEl-targeted gastric cancer therapy has been carried out. The results showed that targeting of AE1 significantly inhibited the growth of gastric cancer cells. In drug-induced mouse gastric cancer model, the detection rate for gastric cancer was decreased from 62% - 70% to 15.8% after knockdown of AE1. AE1 protein, as a target, has important value in diagnosis and treatment of gastric cancer.