Journal
GASTROENTEROLOGY
Volume 144, Issue 7, Pages 1518-U343Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2013.02.027
Keywords
Nuclear Receptors; Liver Growth; Surgery; Metabolism
Categories
Funding
- Italian Association for Cancer Research (AIRC, Milan, Italy) [IG 10416, IG 9168, MFAG 10684]
- Italian Ministry of University and Education (Finanziamenti per la Ricerca di Base IDEAS [RBID08C9N7, PRIN 20085Y7XT5_004]
- Italian Ministry of Health [GR-2008-1143546, GR-2010-2314703]
- University of Bari, Italy [ORBA 08WEZJ, 07X7Q1, 06BXVC, IDEA GRBA0802SJ]
- CariSPAQ
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BACKGROUND & AIMS: Studies of the transcriptional networks that regulate nuclear receptor-mediated proliferation of quiescent hepatocytes could lead to new information about liver growth and hepatoprotective strategies. METHODS: We used quantitative real-time PCR to analyze expression of neuron-derived orphan receptor 1 (Nor-1) and its target genes during liver regeneration after hepatectomy in mice, and in hepatocellular carcinoma (HCC) samples from patients. We used adenoviral vectors to express Nor-1 in normal liver (Ad/CMV/V5-Nor-1), or reduce its level with small hairpin RNAs (Ad/BLOCK-iT/Nor-1 small hairpin RNA) after partial hepatectomy. RESULTS: Levels of Nor-1 messenger RNA and protein, and transcription of Nor-1 target genes (Ccnd1 and Vcam-1), increased during the late priming and proliferative phases of liver regeneration after partial hepatectomy. Levels of NOR-1 messenger RNA and transcription of its target gene CCND1 and of the NOR-1 subfamily member NUR-77 also increased in human HCC samples compared with paired HCC-free tissue. Ad-Nor1small hairpin RNA reduced the hepatocyte proliferation after hepatectomy. Overexpression of Nor-1 in normal livers of mice induced proliferation of quiescent hepatocytes independently of interleukin-6 and tumor necrosis factor-alpha signaling. In gene expression profile analysis, Nor-1 altered expression of genes involved in the cell cycle, proliferation, and tumorigenesis. CONCLUSIONS: In mice, the orphan nuclear receptor Nor-1 activates proliferation of quiescent hepatocytes and is required for hepatocyte proliferation after partial hepatectomy. Nor-1 and its gene targets are also up-regulated in human HCC samples. Nor-1 activates a transcriptional program that induces hepatocyte proliferation independently of inflammatory signaling pathways.
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