HER2/XAF1/MTA1信号通路调控失衡参与胃癌曲妥珠单抗原发耐药的机制研究

Trastuzumab(humanized monoclonal antibody) targeting to HER2 has been successfully used in the treatment of advanced breast cancer. After the completion of the gastric phase III clinical trials, it has been accepted as clinical treatment by the "NCCN Guidelines for Treatment of Gastric Cancer" in 2011. However, many patients were accompanied with primary resistance whose mechanism in gastric cancer has not been reported. In preliminary studies, we found that HER2-MTA1 pathway is closely related to the degree of malignancy in gastric cancer, however just as Small grant of NSFC experts pointed out, the specific mechanism about HER2 regulating MTA1 is still unknown. Preliminary work, we observed that HER2 regulated the expression of MTA1 by XAF1 and trastuzumab XAF1 through different signaling pathway in primary resistance cell line and mediate plays a key role to mediate primary resistance. Based on the differential expression profile of resistant cells, this study will discover key resistance-associated molecule in HER2/XAF1/MTA1 pathway, clarify its detailed regulation mechanism, and analyse how trastuzumab regulates these processes and signaling networks. This study will be useful to recognize molecular mechanisms about trastuzumab primary resistance, and provide a theoretical basis for targeted therapy of HER2-positive gastric cancer.

曲妥珠单抗（Trastuzumab）是靶向HER2的人源化单克隆抗体，已成功应用于晚期乳腺癌治疗，完成胃癌的Ⅲ期临床试验后，于2011年被"胃癌NCCN临床实践指南"录入。然而相当多数患者表现出原发耐药，其机制在胃癌中尚未阐明。前期研究中，我们发现HER2-MTA1通路与胃癌的恶性程度密切相关，然而HER2调控MTA1的具体机制尚属未知。小额资助项目评审专家指出应对其进行研究。本研究预实验中初步了解到HER2通过XAF1调控MTA1的表达，且在曲妥珠单抗原发耐药的细胞株中HER2通过不同的信号通路调控XAF1并对介导耐药起着关键的作用。本研究在已获得耐药细胞差异表达谱的基础上，明确HER2/XAF1/MTA1通路中关键耐药相关分子，阐明其精细调控机制以及曲妥珠单抗对上述过程的调节作用和信号网络，从而有助于系统认识胃癌曲妥珠单抗原发耐药的分子机制，并为HER2阳性肿瘤的靶向治疗提供理伦依据。

曲妥珠单抗（Trastuzumab）是靶向于HER2的人源化单克隆抗体，被批准用于HER2过表达的晚期胃癌的一线治疗。然而相当多数患者表现出原发耐药，其机制在胃癌中尚未阐明。我们发现在曲妥珠单抗敏感的细胞株中HER2是通过抑癌基因XAF1及与其发挥作用密切相关的XIAP这一E3泛素连接酶介导的MTA1泛素化来调节MTA1分子的表达。另人倍感意外的是，在曲妥珠单抗原发耐药细胞株中，其可以通过上调PSMD10分子来下调P53的表达，从而保证MTA1的表达维持在较高水平，抑制细胞的增殖和转移，我们认为这是导致胃癌对曲妥珠单抗原发耐药的原因之一。通过阐明在对曲妥珠单抗治疗敏感性表现出差异的胃癌细胞系中HER2调控MTA1的精细分子机制，明确XAF1、PSMD10及MTA1等相关分子群在胃癌曲妥珠敏感和耐药过程中的生物学功能和作用，为胃癌患者的疗效预测、预后判断以及分子靶向治疗提供更充分的参考依据。