DCA激活FXR增强结直肠癌细胞放射抵抗能力的机制研究

探寻结直肠癌放射抵抗的调控基因，阐明其调控的分子机制是重要的临床问题。我们前期研究发现：直肠癌患者术前放疗后，血清中脱氧胆酸（DCA）明显升高，且DCA可以增强结肠癌的照射抵抗能力，国内外尚未见报道。已有研究表明DCA是法尼酯X受体（FXR）的天然配体。我们前期预实验进一步研究发现：FXR可能可以直接调控核受体GLI2，且抑制GLI2蛋白的表达可以增加结直肠癌细胞的放疗敏感性。基于此，我们提出假说：DCA通过激活FXR，进一步调控GLI2，增强结直肠癌细胞的放射抵抗能力。本项目拟采用靶向代谢组学、Chip、CRISPR-Cas9、生物信息学等实验技术手段，旨在揭示DCA/FXR/GLI2信号轴在结直肠癌放射抵抗中的重要作用，为提高结直肠癌放射敏感性，改善结直肠癌放射治疗疗效提供理论及实验依据。

Exploring the regulatory genes of radiation resistance in colorectal cancer and elucidating the molecular mechanism of its regulation is an important problem in clinical filed. Our previous study found that serum deoxycholic acid (DCA) significantly increased in patients with rectal cancer after preoperative radiotherapy, and DCA can enhance radiation resistance of colon cancer, which has not been reported so far. It has been shown that DCA is a natural ligand for FXR. Our pre-experiment further found that FXR may directly regulate the nuclear receptor Gli2, and inhibiting the expression of Gli2 protein can increase the radiotherapy sensitivity of colorectal cancer cells. Based on this, we hypothesized that DCA further regulates GLI2 and enhances radiation resistance of colorectal cancer cells through activation of FXR. This project intends to use targeted metabonomics, ChIP, CRISPR-Cas9, bioinformatics and other experimental techniques, aiming to reveal the important role of DCA/FXR/GLI2 signal axis in radiation resistance of colorectal cancer, and to provide theoretical and experimental basis for improving radiosensitivity of colorectal cancer and curative effect of radiotherapy of colorectal cancer.