title: Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation.
abstract: An essential regulator of gene transcription, nuclear receptor liver receptor homologue 1 (LRH-1) controls cell differentiation in the developing pancreas and maintains cholesterol homeostasis in adults. Recent genome-wide association studies linked mutations in the LRH-1 gene and its up-stream regulatory regions to development of pancreatic cancer. In this work, we show that LRH-1 transcription is activated up to 30-fold in human pancreatic cancer cells compared to normal pancreatic ductal epithelium. This activation correlates with markedly increased LRH-1 protein expression in human pancreatic ductal adenocarcinomas in vivo. Selective blocking of LRH-1 by receptor specific siRNA significantly inhibits pancreatic cancer cell proliferation in vitro. The inhibition is tracked in part to the attenuation of the receptor's transcriptional targets controlling cell growth, proliferation, and differentiation. Previously, LRH-1 was shown to contribute to formation of intestinal tumors. This study demonstrates the critical involvement of LRH-1 in development and progression of pancreatic cancer, suggesting the LRH-1 receptor as a plausible therapeutic target for treatment of pancreatic ductal adenocarcinomas.
authors.affiliation: Department of Biochemistry and Biophysics, University of California 600 16th Street, GH S412E, San Francisco, CA 94158-2517, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Benod
authors.forename: Maia V
authors.initials: MV
authors.lastname: Vinogradova
authors.forename: Natalia
authors.initials: N
authors.lastname: Jouravel
authors.forename: Grace E
authors.initials: GE
authors.lastname: Kim
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fletterick
authors.forename: Elena P
authors.initials: EP
authors.lastname: Sablin
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004848:Epithelium / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D034741:RNA, Small Interfering / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C082631:NR5A2 protein, human; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear