IL-22/LncRNA信号通路调控代谢重编程介导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 observed IL-22 signal mediated primary resistance through the regulation of metabolic reprogramming, IL-22 upregulated histone H3 acetylation level of G6PD through a novel LncRNA to regulate the expreission fo G6PD, in this study, based on transcriptome differences information in drug resistant tissue, in vitro and genetic engineering mice in vivo model, we will elucidate that detailed mechanism of IL-22/ LncRNA/ G6PD pathway through the molecular biology means, clarify the key resistance-associated molecular, analysis that IL-22 as tumor microenvironment molecule regulates metabolic reprogramming process contributing to Trastuzumab resistance gastric cancer, and help understanding the molecular mechanism of trastuzumab primary resistance in gastric cancers, which will provide a theoretical basis for HER2 positive cancer targeting therapy.

曲妥珠单抗（Trastuzumab）是靶向于HER2的人源化单克隆抗体，已成功应用于晚期乳腺癌治疗，2011年被引入“胃癌NCCN临床实践指南”。然而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，我们观察到炎症信号IL-22可能调控代谢重编程从而介导胃癌曲妥珠单抗原发耐药，初步了解到IL-22通过一个新发现的LncRNA上调组蛋白H3乙酰化水平调控磷酸戊糖途径关键限速酶G6PD的表达，本研究在已获得耐药组织转录组差异信息的基础上，通过体外模型和基因工程小鼠等体内模型，以RNA免疫共沉淀等分子生物学手段逐步分析IL-22/ LncRNA/ G6PD通路精细信号调控机制，明确其中关键耐药相关分子，阐明胃癌肿瘤微环境中IL-22信号通路启动代谢重编程过程相关分子表达与耐药形成的关系，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阳性肿瘤的分子靶向治疗提供理论依据。

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。通过建立肿瘤异种移植动物模型，我们发现在曲妥珠单抗敏感的细胞株中HER2是通过磷酸戊糖途径激活来发挥作用的。在体外实验中，我们观察到JUN、PCAF、和Linc-RT相互作用通过乙酰化机制调控G6PD，从而保证G6PD的表达维持在较高水平，我们通过动物模型等体内研究手段也观察到了类似的现象。通过体内外实验及临床样本分析获得的数据，我们认为这种将淋巴造血系统相关的炎症环境与代谢重编程联系起来的表观遗传学机制可能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G6PD的精细分子机制，我们明确了JUN、PCAF、和Linc-RT1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，并对炎症微环境与胃癌的关系进行了探讨，为未来对淋巴造血系统及包括胃癌在内的更广泛消化系统肿瘤之间的关系进行研究打下一定的理论和实验基础。