ACOX1通过抑制Wnt/β-catenin信号通路抑制结直肠癌发生的机制研究

结直肠癌（colorectal cancer，CRC）是世界第三大流行肿瘤，Wnt/β-catenin信号通路在CRC中频繁激活。代谢改变是肿瘤的典型特征，然而关于CRC代谢改变的研究仍不完善。我们对2752个代谢酶进行系统的生物信息学分析发现ACOX1在CRC中显著低表达，且与CRC患者不良预后相关。此外，ACOX1表达量可作为CRC的诊断标准。我们前期也发现VDR与p53相互作用，上调ACOX1 mRNA水平；DUSP14与ACOX1相互作用，影响ACOX1多聚泛素化水平；ACOX1底物棕榈酸（PA）促进β-catenin蛋白稳定性。基于文献资料和前期实验结果，本项目拟阐明：1.VDR招募p53转录调控ACOX1；2.DUSP14去磷酸化ACOX1而促进其泛素化降解；3.ACOX1通过调控PA抑制Wnt/β-catenin信号通路。总之，这将为CRC的诊疗提供理论依据。

Colorectal cancer (CRC) is the third most prevalent world cancer and the Wnt/β-catenin signaling pathway is frequently activated in CRC. Metabolic alteration has been recognized as a hallmark of cancer, however, the study on metabolic alteration in CRC is still incomplete. We conduct a systematic bioinformatics analysis of 2752 metabolic enzymes and show that ACOX1 is significantly down-regulated and predicts poor prognosis in human patients with CRC. Besides, ACOX1 expression level could be used as a diagnostic marker of CRC. We also find that VDR interacts with p53 to up-regulate ACOX1 mRNA level; DUSP14 interacts with ACOX1 to affect the poly-ubiquitination level of ACOX1; ACOX1's substrate palmitic acid (PA) promotes β-catenin protein stability. Based on literature and preliminary experimental results, this project aims to clarify: 1. VDR recruits p53 to transcriptionally regulate ACOX1; 2. DUSP14 dephosphorylates ACOX1 to promote its ubiquitination degradation; 3. ACOX1 inhibits the Wnt/β-catenin signaling pathway by regulating PA level. Altogether, this will provide a theoretical basis for the diagnosis and treatment of CRC.