AMACR驱动结肠癌细胞胆汁酸代谢促进肝转移的分子机制研究

Due to the poor survive of metastatic colon cancer, it has challenged the clinical treatments critically. Although liver is the most frequent metastatic organ, which has a special bile acid microenvironment, the specific mechanism underlying the liver metastasis of colon cancer remains not determined yet. Our preliminary research results have found that the expression levels of alpha-methylacyl-CoA racemase (AMACR) was specifically upregulated in the liver metastasis of colon cancer, which promoted the liver metastasis in colon cancer. Secondly, AMACR not only inhibited oxidative stress and decreased apoptosis, but also increased colony formation in the microenvironment with bile acid, which resulted in the promotion of liver metastasis in colon cancer. Thirdly, the deregulation of Wnt pathway induced the expression of FXR, which upregulated the AMACR with the help of bile acid. However, the specific mechanism remains further investigated. Hence, we hypothesis that under the circumstance of bile acid, colon cancer upregulated the expression of FXR and AMACR, which promote the oxidation of bile acid, enhance the adaption to bile acid environment and finally lead to the formation of liver metastasis. Based on the above founding, we will further utilize cell and animal model, metabonomics transcriptomic technique, molecular biological technique and nanomaterial to investigate the specific functions and mechanisms in the process of liver metastasis and design an effect inhibitor which target to AMACR. Accordingly, the successful implementation of this project will provide novel auxiliary diagnostic molecule and potential therapeutic target to conquer the liver metastasis of colon cancer.

转移性结肠癌患者因其预后不良导致临床治疗面临严峻的挑战,肝脏不仅是结肠癌最常见的转移器官，且具有特殊的胆汁酸微环境，然而，目前对于结肠癌肝转移的分子机制尚不清楚。我们的前期研究发现：1、AMACR在结肠癌肝转移中特异性高表达，并促进结肠癌肝转移；2、AMACR可减少胆汁酸诱导的氧应激，抑制凋亡，增强克隆增殖；3、Wnt信号通路的异常激活可上调FXR的表达，胆汁酸与FXR结合转录上调AMACR，随后AMACR可促进胆汁酸的氧化分解。但尚不清楚AMACR通过胆汁酸代谢促进结肠癌肝转移灶形成的具体分子机制。因此，我们假设，在胆汁酸微环境中，结肠癌细胞上调FXR和AMACR的表达，促进胆汁酸的氧化分解，提高细胞对胆汁酸微环境的适应，促进肝转移灶的形成。本项目在此基础上，拟进一步阐明AMACR促进结肠癌肝转移的详细分子机制，为结肠癌肝转移的早期诊治提供新的生物标记物及治疗靶点。

转移性结肠癌患者的预后差，其临床治疗面临着严峻的挑战。肝脏是结肠癌最常见的转移器官，具有特殊的胆汁酸循环微环境，目前对于结肠癌肝转移的分子特征尚不清楚。我们前期研究发现，α甲基酰基辅酶A消旋酶（AMACR）在结肠癌肝转移中特异性性高表达，且其高表达预示着患者更短的生存时间。细胞及动物实验中，发现过表达AMACR能调控肿瘤细胞的胆汁酸代谢，促进肿瘤细胞的克隆增殖，最终导致结肠癌肝转移。但AMACR促进结肠癌细胞胆汁酸代谢的机制尚待进一步探索。本项目的开展明确了以下内容：1、利用代谢组学检测，明确AMACR促进肠癌细胞的胆汁酸代谢。2、运用细胞学实验证明了AMACR可促进结肠癌细胞的存活、增强肿瘤细胞的克隆增殖。3、小鼠动物实验明确了AMACR促进结肠癌细胞肝转移。4、细胞生物学实验明确了AMACR促进肠癌细胞的过氧化物酶体的氧化代谢。5、分子生物学实验揭示了FXR与RXRA协同转录上调AMACR。6、生信分析及相关分子生物实验验证了异常激活的WNT信号通路通过FOS转录调控FXR。7、生信分析揭示了结肠癌患者中AMACR的高表达，与基因的拷贝数变异相关。本项目的开展明确了AMACR促进肿瘤细胞胆汁酸代谢的生物学作用及分子机制，为临床结肠癌肝转移的早期诊治提供新的生物标记物及治疗靶点。