Abstract
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.
Highlights
Nuclear receptors (NRs) are a class of transcription factors that regulate gene expression in a spatiotemporal manner, thereby controlling differentiation, homeostasis and metabolism
We investigated the relationship between orphan NRs and bladder cancer progression
We studied the expression of 22 orphan NRs in paired clinical bladder cancer tissues and adjacent normal tissues from the same patients
Summary
Nuclear receptors (NRs) are a class of transcription factors that regulate gene expression in a spatiotemporal manner, thereby controlling differentiation, homeostasis and metabolism. Bladder cancer can be categorized into two major clinicopathologically different tumor subtypes: superficial, non-muscle-invasive type and advanced, muscle-invasive type.[3] Patients with superficial bladder cancer are usually treated with transurethral resection with or without intravesical chemotherapy and have a favorable prognosis; some of these patients suffer from recurrence with grade progression. Patients with advanced bladder cancer are treated with more aggressive therapeutic options such as radical cystectomy and urinary diversion with or without chemotherapy; these patients have a less favorable prognosis with a 5-year survival rate of approximately 50% in the United States of America.[4] Clinicopathological parameters such as grade, stage and invasion provide important prognostic information but are not sufficient for the precise prediction of recurrence or survival in patients with bladder cancer. Novel biomarkers that predict and therapeutic options that prevent the progression of this disease need to be developed
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