Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-10, Vol.108 (41), p.16927-16931
• Main Authors: Benod, Cindy, Vinogradova, Maia V., Jouravel, Natalia, Kim, Grace E., Fletterick, Robert J., Sablin, Elena P.
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Biological Sciences; Cancer; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Carcinoma, Pancreatic Ductal - physiopathology; Cell cycle; Cell Cycle Checkpoints; Cell growth; Cell Line, Tumor; Cell lines; Cell Proliferation; Epithelium - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Homeostasis; Humans; Liver; Models, Biological; Mutation; Nuclear receptors; Pancreas - metabolism; Pancreatic cancer; Pancreatic cells; Pancreatic neoplasms; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - physiopathology; Receptors; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - physiology; RNA, Small Interfering - genetics; Signal Transduction; Small interfering RNA; T cell receptors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1112047108

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 du eta I 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.