Nuclear receptors (NRs) are a class of
transcription factors that are closely involved in the progression of certain types of
cancer. We aimed to study the relation between
bladder cancer and NRs, with special focus on orphan NRs whose
ligands and functions have not been identified. First, we examined the expression levels of 22 genes encoding orphan NRs in clinical
bladder cancer and found that
hepatocyte nuclear factor 4γ (HNF4G; NR2A2) and NR2F6 were the genes that were upregulated most frequently in
cancer tissues compared with their paired normal tissues. Knockdown and overexpression of each of these orphan NRs suppressed and stimulated the growth of
bladder cancer cells in vitro, respectively. HNF4G also promoted
tumor growth in
bladder cancer xenograft models in vivo. Furthermore, HNF4G was both necessary and sufficient for the invasion of
bladder cancer cells in vitro. Moreover, using microarray analyses, we identified
hyaluronan synthase 2 (HAS2) as one of the genes induced by HNF4G in
bladder cancer cells. Transcription was activated by HNF4G in reporter assays using the promoter/enhancer region of the HAS2 gene. The endogenous expression of the HAS2 gene was suppressed by knockdown of HNF4G. In turn, knockdown of HAS2 inhibited the growth and invasion of
bladder cancer cells. Taken together, our data suggest that some orphan NRs are involved in
bladder cancer progression and that, among them, HNF4G promotes the growth and invasion of
bladder cancer, at least in part, via the regulation of the HAS2 gene.