Beijing Key Laboratory of Gene Resource and Molecular Development and College of Life Sciences, Beijing Normal University, Beijing, People's Republic of China; Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an, China;
Beijing Key Laboratory of Gene Resource and Molecular Development and College of Life Sciences, Beijing Normal University, Beijing, People's Republic of China;
Am J Physiol Cell Physiol. 2015 Mar 1;308(5):C385-96. doi: 10.1152/ajpcell.00091.2014. Epub 2014 Dec 10.
Lipid metabolic disturbances are related to many diseases, such as obesity, diabetes, and certain cancers. Notably, lipid metabolic disturbances have been reported to be a risk factor for colorectal cancer. Nuclear receptors act as ligand-dependent transcription regulators and play key roles in the regulation of body lipid metabolism and the development of many cancers. Retinoic acid receptor-related orphan receptor α (RORα) is a nuclear receptor and can regulate several lipid metabolism genes in certain cancers. Herein, we demonstrate that the conditioned medium from adipocytes has a proproliferative and promigratory effect on colorectal cancer cells and enhances angiogenesis in chicken embryonic chorioallantoic membranes. In addition, the conditioned medium leads to a decrease in the expression of RORα and its target genes. Meanwhile, RORα and its target gene expressions are lower in human colorectal tumor tissue compared with control colorectal tissue. Activation of RORα inhibits the effect of conditioned medium on the proliferation and migration of colorectal cancer cells as well as the angiogenesis in chicken embryonic allantoic membranes. In colorectal cancer cells, the putative ligand of RORα, cholesterol sulfate (CS), prevents cell cycle progression at the G1/S boundary and concurrently modulates the expression of cell cycle-regulatory genes in colorectal cancer cell. CS inhibits angiogenesis in chicken embryonic chorioallantoic membranes and concurrently decreases the mRNA expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α as well as the secretion of VEGF. In addition, lipogenic gene expression is higher in human colorectal tumor tissue compared with control colorectal tissue. CS inhibits the expression of lipogenic genes in colorectal cancer cells. These results suggest that RORα could represent a direct link between local lipid metabolism of colorectal tissue and colorectal cancer. Therefore, the reduction of the expression of RORα could represent a potential warning sign of colorectal cancer.
脂质代谢紊乱与许多疾病有关，如肥胖、糖尿病和某些癌症。值得注意的是，脂质代谢紊乱已被报道为结直肠癌的一个风险因素。核受体作为配体依赖性转录调节剂，在调节机体脂质代谢和多种癌症的发生发展中发挥着关键作用。维甲酸受体相关孤儿受体α（RORα）是一种核受体，可在某些癌症中调节几种脂质代谢基因。本文中，我们证明脂肪细胞的条件培养基对结直肠癌细胞具有促增殖和促迁移作用，并增强鸡胚绒毛尿囊膜的血管生成。此外，条件培养基导致 RORα及其靶基因的表达减少。同时，与对照结直肠组织相比，人结直肠肿瘤组织中 RORα及其靶基因的表达水平较低。RORα 的激活抑制了条件培养基对结直肠癌细胞增殖和迁移以及鸡胚绒毛尿囊膜血管生成的影响。在结直肠癌细胞中，RORα 的假定配体胆固醇硫酸盐（CS）可阻止细胞周期在 G1/S 交界处的进展，并同时调节结直肠癌细胞中细胞周期调节基因的表达。CS 抑制鸡胚绒毛尿囊膜中的血管生成，并同时降低血管内皮生长因子（VEGF）和缺氧诱导因子-1α的 mRNA 表达以及 VEGF 的分泌。此外，与对照结直肠组织相比，人结直肠肿瘤组织中的脂肪生成基因表达更高。CS 抑制结直肠癌细胞中脂肪生成基因的表达。这些结果表明，RORα 可能是结直肠组织局部脂质代谢与结直肠癌之间的直接联系。因此，RORα 表达的减少可能代表结直肠癌的一个潜在预警信号。
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