基于FGF/FGFR介导PI3K/Akt信号通路探讨结直肠癌化疗耐药机制及健脾消癌方化疗增效作用机制研究

PI3K/Akt signal pathway usually abnormal activation in colorectal cancer, relate to the chemotherapy drug resistanceis closely. Fibroblast growth factor (FGF) expressed in tumor cells, and also has a certain relationship with tumor drug resistance, but the resistance mechanism is still not entirely clear, it can activate PI3K/Akt signal pathway, whether FGF involved in resistance by activating PI3K/Akt signal pathway or not, need further exploration. Preliminary clinical study suggests Jianpi Xiaoai Decoction with chemotherapy effect is better than pure chemotherapy, it have a synergistic effect with chemotherapy, maybe the mechanism of synergy is inhibiting or reversing resistance. This research establish HCT116/5-FU resistant strains, detect FGF expression, and promote and inhibit FGF expression, clarifying its relevance to drug resistance in colorectal cancer, and observe influence on PI3K/Akt signal pathway, so as to determine whether FGF involved in resistance by activating PI3K/Akt signaling pathway. To Jianpi Xiaoai Decoction intervention, discusses it plays chemotherapy synergy whether by inhibiting or reversing resistance, explore the molecular mechanism of its regulation resistance, whether through regulating FGF influence PI3K/Akt signal pathway, so as to provide scientific basis for clinical.

结直肠癌细胞中PI3K/Akt信号通路通常存在着异常激活，与肿瘤耐药的发生关系密切。纤维母细胞生长因子（FGF）在肿瘤细胞中表达，与肿瘤耐药也有一定关系，但参与耐药机制仍未完全明确，其可以激活PI3K/Akt信号通路，FGF参与耐药是否通过激活PI3K/Akt发挥耐药作用，有待进一步探索。前期临床研究提示健脾消癌方配合化疗疗效优于单纯化疗，具有化疗增效作用，增效的机制可能是抑制或逆转耐药。本研究建立HCT116/5-FU耐药株，检测FGF表达，并促进及抑制FGF表达，明确其与结直肠癌耐药性的相关性，观察对PI3K/Akt信号通路影响，从而明确FGF参与耐药是否通过激活PI3K/Akt信号通路发生。以健脾消癌方干预，探讨健脾消癌方是否通过抑制或逆转耐药发挥化疗增效作用，探索其调控耐药的分子机制，是否通过调控FGF影响PI3K/Akt信号通路，以期为临床提供科学依据。

结直肠癌细胞中PI3K/Akt信号通路通常存在着异常激活，与肿瘤耐药的发生关系密切。纤维母细胞生长因子（FGF）在肿瘤细胞中表达，与肿瘤耐药也有一定关系，但参与耐药机制仍未完全明确，其可以激活PI3K/Akt信号通路，FGF参与耐药是否通过激活PI3K/Akt发挥耐药作用，有待进一步探索。前期临床研究提示健脾消癌方配合化疗疗效优于单纯化疗，具有化疗增效作用，增效的机制可能是抑制或逆转耐药。本研究建立HCT116/5-FU耐药株，检测FGF表达，并促进及抑制FGF表达，明确其与结直肠癌耐药性的相关性，观察对PI3K/Akt信号通路影响，从而明确FGF参与耐药是否通过激活PI3K/Akt信号通路发生。以健脾消癌方干预，探讨健脾消癌方是否通过抑制或逆转耐药发挥化疗增效作用，探索其调控耐药的分子机制，是否通过调控FGF影响PI3K/Akt信号通路，以期为临床提供科学依据。. 研究结果发现耐药细胞中FGF2、p-FGFR1高表达，耐药细胞组、FGF2重组蛋白组细胞存活率增高，p-PI3K、p-Akt、p-mTOR表达上调，Bad蛋白表达下调；FGFR抑制剂组细胞存活率降低，p-PI3K、p-Akt、p-mTOR表达下调，Bad蛋白表达上调；提示FGF2/FGFR主要通过活化PI3K下游的Akt/mTOR、Akt/Bad通路参与耐药。. 健脾消癌方干预耐药细胞，细胞存活率下降，健脾消癌方各浓度组FGF2、p-FGFR1表达下调，p-Akt、p-mTOR表达下调，Akt、NF-κB、Bad、FKHR表达上调；动物实验方面，建立裸鼠耐药细胞移植瘤模型，分组干预，研究发现健脾消癌方联合5-Fu组抑制耐药瘤体疗效优于单纯的健脾消癌组、5-Fu组，FGF2、p-FGFR1表达下调，p-PI3K、p-Akt、p-mTOR表达下调，Bad蛋白表达上调，说明健脾消癌方联合化疗有增效作用，可能是改善耐药，其机制可能是抑制FGF2/FGFR信号通路，下调PI3K/Akt信号通路。. 本研究揭示了中医药治疗结直肠癌的机制，中医药联合化疗通过改善耐药发挥增效作用，为有利于结直肠癌临床疗效提高，延长患者生存期。