Modulation of expression of the nuclear receptor NR0B2 (small heterodimer partner 1) and its impact on proliferation of renal carcinoma cells

Abstract

Mammalian nuclear receptors (NRs) are transcription factors regulating the expression of target genes that play an important role in drug metabolism, transport, and cellular signaling pathways. The orphan and structurally unique receptor small heterodimer partner 1 (syn NR0B2) is not only known for its modulation of drug response, but has also been reported to be involved in hepatocellular carcinogenesis. Indeed, previous studies show that NR0B2 is downregulated in human hepatocellular carcinoma, suggesting that NR0B2 acts as a tumor suppressor via inhibition of cellular growth and activation of apoptosis in this tumor entity. The aim of our study was to elucidate whether NR0B2 may also play a role in other tumor entities. Comparing NR0B2 expression in renal cell carcinoma and adjacent nonmalignant transformed tissue revealed significant downregulation in vivo. Additionally, the impact of heterologous expression of NR0B2 on cell cycle progression and proliferation in cells of renal origin was characterized. Monitoring fluorescence intensity of resazurin turnover in RCC-EW cells revealed no significant differences in metabolic activity in the presence of NR0B2. However, there was a significant decrease of cellular proliferation in cells overexpressing this NR, and NR0B2 was more efficient than currently used antiproliferative agents. Furthermore, flow cytometry analysis showed that heterologous overexpression of NR0B2 significantly reduced the amount of cells passing the G1 phase, while on the other hand, more cells in S/G2 phase were detected. Taken together, our data suggest that downregulation of NR0B2 may also play a role in renal cell carcinoma development and progression.

The Orphan Nuclear Receptor Gene NR0B2 Is a Favorite Prognosis Factor Modulated by Multiple Cellular Signal Pathways in Human Liver Cancers

“…Our data confirmed the predominant expression profile of the NR0B2 gene in benign liver and kidney tissues. Interestingly, NR0B2 expression was significantly downregulated in malignant tissues derived from these organs, consistent with previous reports (10,14,43), indicating a dramatic alteration in regulating NR0B2 gene expression after malignant transformation. Higher NR0B2 expression is associated with fewer disease relapse and progression in liver cancer patients and is also associated with a favorite overall survival prognosis in human breast cancers, lung adenocarcinomas, liposarcomas, and eye uveal melanomas.…”

“…There is a paucity of NR0B2 expression from human cancer specimens, and so far, only two reports showed NR0B2 downregulation in 10 cases of liver cancers (HCC) ( 14) and 24 cases of renal cancers (RCC) (10). With the advance of bioinformatic technologies, many public databases are assessable to analyze gene expression profiles in a variety of human cancers.…”

“…It acts as a transcriptional repressor by binding to other nuclear receptors to regulate various metabolic pathways, including glucose, bile acid, cholesterol, and fatty acid homeostasis in the organs of the liver, pancreas, and kidney (8). It was reported that NR0B2 gene expression was significantly reduced in liver and kidney cancers and that overexpression of NR0B2 protein suppresses liver cancer development, indicating it is a tumor suppressor (9,10). However, it is not clear if NR0B2 expression is also altered in other human cancer types and if the alteration is associated with patient disease history or outcome.…”

The orphan nuclear receptor NR0B2 could be a novel susceptibility locus associated with microsatellite‐stable, APC mutation‐negative early‐onset colorectal carcinomas with metabolic manifestation

“…It is widely expressed in many organs that play an essential role in development, cellular homeostasis, and disease including cancer where over‐ or under‐expression of some receptors has prognostic significance for cancer patient survival as reviewed 27,42 . Recent studies have implicated NR0B2 ' s tumor suppressor role in renal carcinoma, breast, prostate and also liver cancer, summarized in Supplementary Table S3 20,42‐48 . In elaboration, He et al 45 reported extensive methylation of NR0B2 and downregulation of NR0B2 mRNA expression in human hepatocellular carcinoma (HCC) tissues compared to adjacent healthy tissues.…”

“…Yang et al 49 showed that overexpression of NR0B2 in HCC cells inhibits invasion and migration, and expression of NR0B2 is negatively associated with cancer metastasis in human HCC and gastric cancer. Prestin et al 43 reported downregulation of NR0B2 in human renal cell carcinoma compared to adjacent healthy tissues. Nevertheless, the underlying mechanisms that trigger altered expression of NR0B2 in specific tumors has not been reported, and there are currently no germline NR0B2 variants known to be associated with cancer.…”