Orphan receptor small heterodimer partner suppresses tumorigenesis by modulating cyclin D1 expression and cellular proliferation.
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.


CONCLUSIONS
These results provide first evidence that SHP plays tumor suppressor function by negatively regulating cellular growth.
Department of Medicine and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84132, USA.
Yuxia
Y
Zhang
Ping
P
Xu
Kyungtae
K
Park
Yunhee
Y
Choi
David D
DD
Moore
Li
L
Wang
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D009369:Neoplasms / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000378:metabolism*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*; D015854:Up-Regulation
D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D025521:Tumor Suppressor Proteins; C099713:nuclear receptor subfamily 0, group B, member 2; D019938:Cyclin D1