细胞外基质蛋白FGA调控肺腺癌培美曲塞耐药的作用和机制研究

肿瘤耐药是导致治疗失败和疾病进展的主要原因，培美曲塞是肺腺癌的首选化疗药物，明确耐药机制建立逆转耐药措施有重要的理论和临床应用价值。分泌蛋白与化疗药物的获得性耐药等病理状态密切相关。前期研究发现，细胞外基质蛋白-纤维蛋白原α(FGA)在原发或继发性培美曲塞耐药的肺腺癌患者中均表达升高，提示FGA可能是肺腺癌化疗中培美曲塞耐药的重要调控分子。由于FGA与跨膜受体整合素β1相互作用，提示FGA可能通过跨膜受体整合素传递胞外基质信号。由此我们提出：细胞外基质蛋白FGA可能通过调控跨膜受体整合素传递的胞外基质信号，从而导致肺腺癌化疗中培美曲塞耐药。本课题将从调控分子-细胞系-动物模型-患者样本等四个层次阐明FGA/整合素β1信号级联调节肺腺癌化疗中培美曲塞耐药的分子机制。本研究将为揭示肺腺癌患者化疗药物耐药的分子机制提供理论依据，并有望为预测和改善肺腺癌患者的化疗疗效提供新的治疗策略。

Drug resistance of tumor is the main cause of treatment failure and disease progression. Pemetrexed is the first choice of chemotherapy drug for lung adenocarcinoma, thus it will be great theoretical and clinical value of pemetrexed to clarify the mechanism of its drug resistance and establish measures to reverse drug resistance. Secreted protein is highly related to acquired drug resistance of chemotherapy drugs and other pathological conditions. Our previous studies have found that the expression of extracellular matrix protein-Fibrinogen Alpha Chain (FGA) was significantly increased in lung adenocarcinoma patients with primary or secondary pemetrexed resistant, thus FGA may be an important regulatory molecule for pemetrexed resistant of lung adenocarcinoma. Meanwhile, there is an interaction between FGA and transmembrane receptor integrin β1, which suggests that FGA can transmit extracellular matrix signals through transmembrane receptor integrin. Therefore, it is proposed that extracellular matrix protein FGA may cause pemetrexed-resistance in the chemotherapy of lung adenocarcinoma through regulating transmembrane receptor integrin mediated-transmission of extracellular matrix signals. In this project, we aim to elucidate the molecular mechanism of FGA/transmembrane receptor integrin β1 signaling pathway on drug resistance in patients with lung adenocarcinoma from evidences in cell culture, animal model and clinical patients. It will provide the theoretical basis to reveal the molecular mechanism of drug resistance in lung adenocarcinoma patients with chemotherapy, and is expected to develop new treatment strategies to predict and improve chemotherapy curative effect in these patients.