8431

NR0B2

SHP|SHP1;nuclear receptor subfamily 0, group B, member 2;NR0B2;nuclear receptor subfamily 0, group B, member 2

nuclear receptor SHP|nuclear receptor subfamily 0 group B member 2|orphan nuclear receptor SHP|small heterodimer partner

1p36.1

protein-coding

Count: 2; Pubmed_search,Generif

Nuclear receptors (NRs) play pivotal roles in cell growth, proliferation, differentiation and homeostasis. Recent progress demonstrates that NR is tightly linked to human disease such as cancer, diabetes and obesity. Here we explore NR expression profiles in human tissue using systematic approaches. NR gene profiles reveal that individual NR has its own gene expression signature depending on tissue type. Of many organs, NRs expression is enriched in liver. expression of many NRs was significantly changed in liver cancer. Notably, NR0B2/SHP expression level was significantly decreased in human liver cancer but not in normal liver. In addition, expression of SHP is well associated with good prognosis. SHP gene network analysis based on microarray data in liver cancer shows that SHP regulates cell proliferation and metabolism related gene sets. Our systematic approaches suggest that loss of SHP expression in liver might be key genetic events during hepatocarcinogenesis.

BACKGROUND & AIMS: Aberrant hypermethylation of promoter regions in cytosine-guanine dinucleotides (CpG) islands has been shown to be associated with transcriptional silencing of tumor-suppressor genes in many cancers. This study evaluated the methylation profile and the tumor-suppressive function of the small heterodimer partner (SHP, NR0B2) in the development of human hepatocellular carcinoma (HCC). METHODS: Human HCC pathologic specimens and cell lines were used as model systems in this study. RESULTS: The expression of SHP is diminished in HCC pathologic specimens and cell lines by epigenetic silencing owing to SHP promoter hypermethylation. In vitro methylation decreased SHP promoter transactivation and nuclear receptor LRH-1 binding, an event that was reversed by demethylation. Overexpression of SHP inhibited HCC foci formation, arrested HCC tumor growth in xenografted nude mice, and increased the sensitivity of HCC cells to apoptotic stimuli. Further analysis of a total of 19 normal liver and 57 HCC specimens showed that down-regulation of SHP gene expression may be a common denominator of HCC. CONCLUSIONS: We propose that SHP functions as a novel tumor suppressor in the development of HCC. These findings provide new insight into the molecular mechanisms leading to this common cancer and may have both diagnostic and therapeutic applications.

The small heterodimer partner (SHP; NROB2), a member of the nuclear receptor superfamily, contributes to the biological regulation of several major functions of the liver. However, the role of SHP in cellular proliferation and tumorigenesis has not been investigated before. Here we report that SHP negatively regulates tumorigenesis both in vivo and in vitro. SHP-/- mice aged 12 to 15 months old developed spontaneous hepatocellular carcinoma, which was found to be strongly associated with enhanced hepatocyte proliferation and increased cyclin D1 expression. In contrast, overexpressing SHP in hepatocytes of SHP-transgenic mice reversed this effect. Embryonic fibroblasts lacking SHP showed enhanced proliferation and produced increased cyclin D1 messenger RNA and protein, and SHP was shown to be a direct negative regulator of cyclin D1 gene transcription. The immortal SHP-/- fibroblasts displayed characteristics of malignant transformed cells and formed tumors in nude mice. CONCLUSION: These results provide first evidence that SHP plays tumor suppressor function by negatively regulating cellular growth.