机体脂质代谢异常与肥胖、糖尿病、心血管疾病和肿瘤等众多重大疾病的发生密切相关。结直肠癌是当今世界上最常见和致死率极高的恶性肿瘤之一。因此，揭示结直肠癌的发病机理，探寻有效的结直肠肿瘤治疗方案是研究工作者面临的迫切任务。研究表明，肥胖与众多癌症的高发性密切相关。核受体作为配体依赖性的转录调控因子在机体脂质代谢调控和肿瘤发生中发挥关键作用。视黄酸相关孤儿核受体α（RORα）作为一类重要的脂质代谢性核受体，不仅在机体脂质代谢稳态调控中具有重要的功能，且参与了许多肿瘤的发生。本研究针对RORα是否参与结直肠局部脂质代谢的调控从而影响结直肠癌的发生这一核心问题，通过配体药理性激活RORα的表达，分别从组织和细胞水平研究RORα对结直肠局部脂质代谢稳态的调控以及对结直肠癌发生的影响，阐释RORα在结直肠癌发生中的作用机制。 首先，本研究收集小鼠脂肪细胞分泌物来模拟体内生理水平的脂肪因子。通过计数、Tanswell和鸡胚绒毛尿囊膜血管形成实验等方法，观察脂肪细胞分泌物对人结直肠癌细胞SW480和小鼠结直肠癌细胞C26的增殖、迁移和鸡胚绒毛尿囊膜血管形成能力的影响。实验结果表明：小鼠脂肪细胞分泌物在体外能同时促进SW480和C26细胞的增殖、迁移和鸡胚绒毛尿囊膜血管形成能力。其次，采用Wstern Blot 和Real-time PCR实验方法观察RORα及其下游靶基因在人和小鼠结直肠组织中的表达情况。实验结果表明：RORα及其下游靶基因在人和小鼠结直肠正常组织中的表达明显高于其在癌组织中的表达。再次，采用MTT、细胞计数、流式细胞术、Transwell、Wstern Blot 、Real-time PCR、ELISA等实验方法，观察药理性激活RORα对SW480和C26的增殖、迁移和鸡胚绒毛尿囊膜血管形成能力的影响。实验结果显示：在SW480和C26细胞中，药理性激活RORα均能剂量依赖性的抑制结直肠癌细胞的体外增殖、迁移和鸡胚绒毛尿囊膜血管形成能力；进一步的分子机制研究表明，药理性激活RORα对结直肠癌细胞的增殖作用可能是通过调控和细胞周期相关的基因的mRNA和蛋白水平的表达来实现，同时，药理性激活RORα对鸡胚绒毛尿囊膜血管形成的抑制作用是通过抑制了HIF-1α和VEGF的mRNA水平的表达以及VEGF蛋白水平的表达来实现。最后，采用Real-time PCR实验方法检测了人和小鼠结直肠正常组织和癌组织中脂肪酸合成相关基因的表达情况，结果显示：在人和小鼠结直肠癌组织中脂肪酸合成的基因表达水平都高于其在正常组织中的表达，且药理性激活RORα可以抑制结直肠癌细胞中脂肪酸合成基因的表达。综上，我们的研究证实了RORα在结直肠脂质代谢调控和肿瘤发生中是一个重要的转录因子，为RORα参与机体脂质代谢的调控和肿瘤的发生奠定理论基础，提出了RORα可作为结直肠癌临床诊断和治疗的潜在预警靶标。

Lipid metabolism plays many roles in body which related to much disease such as obesity, diabetes, cardiovascular disease and tumor development. Colorectal cancer is one of the most common and lethal diseases in the world. Therefore, understanding the pathogenesis of colorectal cancer, and exploring the effective treatment scheme are the urgent tasks to the colorectal cancer related researchers. It has been reported that obesity is a risk factor for many cancers. Nuclear receptors as ligand-dependent transcription regulators play key roles in body lipid metabolism. Retinoic acid receptor-related orphan receptor α (RORα) as a lipid metabolism nuclear receptor not only exerts roles in body lipid metabolism homeostasis regulation, but also related to many tumor development. The focus of this project is to dissect if RORα is involved in lipid metabolism and also effected on colorectal cancer development. By pharmacological activation of RORα to investigate its effects on the regulation of lipid metabolism homeostasis and colorectal cancer development at the tissue and cellular levels, to elucidate the roles of RORα in colon rectal cancer development and to identify several key genes regulated by RORα. Here, we show that adipocytokines from mouse adipocytes not only have the effects of pro-proliferative and pro- migrative effects on colorectal cancer cells, but also can enhance the angiogenesis in chicken embryonic allanto. RORα and its tagart genes expression is lower in human and mouse colorectal tumor tissue as compared to control colorectal tissue. Activation of RORα blunts the effect of adipocytokines on the proliferation and migration of colorectal cancer cells and angiogenesis in chicken embryonic allanto. In colorectal cancer cells, RORα prevented cell cycle progression at the G1/S boundary and concurrently alters the expression of cyclin-dependent kinase inhibitors. RORα restraints the angiogenesis in chicken embryonic allanto and concurrently decreases mRNA expression of VEGF and HIF-1α and the protein level of VEGF. In addition, the lipid metabolism genes expression is higher in human and mouse colorectal tumor tissue as compared to control colorectal tissue. RORα inhibits the expression of lipogenic genes in colorectal cancer cell. These results suggest that RORα could represent a direct link between local lipid metabolism of colorectal tissue and colorectal cancer. Therefore, RORα could represent a potential target for diagnosis and therapy of colorectal cancer. The work laid the foundation for further study the roles of RORα in lipid metabolism homeostasis regulation and tumor development.