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.