巨噬细胞EGFR信号轴活化对小檗碱抗结直肠癌作用的影响

Nowadays the incidence of colorectal cancer (CRC) increases year after year and CRC is difficult for prevention and treatment. Macrophages are involved in tumor progression and metastasis in tumor microenvironment. Increased expression of epidermal growth factor receptor (EGFR) promotes the growth and metastasis of CRC. Activation of EGFR in macrophages and its mechanism for regulating anti-tumor immune response have not been elucidated. Our previous studies demonstrated that berberine (BER) can inhibit the growth of colon cancer cells and found that EGFR expression of macrophages in human colorectal adenocarcinoma increased. The growth.of CRC in macrophages EGFR knockout (Egfrfl/flLysM-Cre) mice can be inhibited and the effect of BER for inhibiting the growth of CRC in Egfrfl/flLysM-Cre mice has been enhanced compared with macrophages EGFR expression (LysM-Cre) mice. Thus, we hypothesize that the proliferation of CRC cells, inhibition of apoptosis and carcinogenesis can be promoted through EGFR signaling pathway in macrophages and that inhibition of this pathway can enhance the effects of anti-colorectal cancer by BER. Our proposal is to demonstrate the relationship and mechanism of the expression of EGFR in macrophages and the carcinogenesis of CRC, then further investigate the effects and mechanism of EGFR expression in macrophages on the role of anti-colorectal cancer by BER using Transwell co-culture, gene chip technology with IMCE-Ras cell line and Egfrfl/flLysM-Cre mice model on protein, nucleic acid, cellular and animal level. This project will provide new evidences and targets for the treatment of CRC.

结直肠癌发病逐年增高，防治困难。巨噬细胞在肿瘤微环境中参与肿瘤进展和转移。EGFR表达升高促进结直肠癌生长和转移。巨噬细胞中EGFR活化后如何调节抗肿瘤免疫应答尚未阐明。我们前期研究证实小檗碱可抑制结肠癌细胞生长，发现人结直肠腺癌组织中巨噬细胞中EGFR表达增高，巨噬细胞敲除EGFR能抑制小鼠结直肠癌发生，并增强小檗碱对小鼠结直肠癌生长的抑制作用。故我们推断“巨噬细胞通过其EGFR信号通路活化，促进结直肠癌细胞增殖、抑制凋亡而导致癌变，抑制该通路可增强小檗碱的抗结直肠癌作用”。本项目利用IMCE-Ras细胞系及巨噬细胞EGFR基因缺陷小鼠为研究对象，利用Transwell共培养、基因芯片等技术在蛋白质、核酸、细胞和动物水平上论证巨噬细胞EGFR表达与结直肠癌发生的关系及机制后，探讨巨噬细胞EGFR表达对小檗碱抗结直肠癌作用的影响及机制，为结直肠癌治疗提供新依据、开拓新靶点。

结直肠癌发病逐年增高，防治困难。巨噬细胞在肿瘤微环境中参与肿瘤进展和转移。EGFR表达升高促进结直肠癌生长和转移。巨噬细胞中EGFR活化后如何调节抗肿瘤免疫应答尚未阐明。我们前期研究证实小檗碱可抑制结肠癌细胞生长，发现人结直肠腺癌组织中巨噬细胞中EGFR表达增高，巨噬细胞敲除EGFR能抑制小鼠结直肠癌发生，并增强小檗碱对小鼠结直肠癌生长的抑制作用。故我们推断“巨噬细胞通过其EGFR信号通路活化，促进结直肠癌细胞增殖、抑制凋亡而导致癌变，抑制该通路可增强小檗碱的抗结直肠癌作用”。本项目利用IMCE-Ras细胞系及巨噬细胞EGFR基因缺陷小鼠为研究对象，利用Transwell共培养、基因芯片等技术在蛋白质、核酸、细胞和动物水平上论证巨噬细胞EGFR表达与结直肠癌发生的关系及机制后，探讨巨噬细胞EGFR表达对小檗碱抗结直肠癌作用的影响及机制，为结直肠癌治疗提供新依据、开拓新靶点。