title: Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs.
abstract: Colorectal cancers (CRCs) account for nearly 10% of all cancer deaths in industrialized countries. Recent evidence points to a central role for the nuclear receptor liver receptor homolog-1 (LRH-1) in intestinal tumorigenesis. Interaction of LRH-1 with the Wnt/β-catenin pathway, highly active in a critical subpopulation of CRC cells, underscores the importance of elucidating LRH-1's role in this disease. Reduction of LRH-1 diminishes tumor burden in murine models of CRC; however, it is not known whether LRH-1 is required for tumorigenesis, for proliferation, or for both. In this work, we address this question through shRNA-mediated silencing of LRH-1 in established CRC cell lines. LRH-1 mRNA knockdown results in significantly impaired proliferation in a cell line highly expressing the receptor and more modest impairment in a cell line with moderate LRH-1 expression. Cell-cycle analysis shows prolongation of G0/G1 with LRH-1 silencing, consistent with LRH-1 cell-cycle influences in other tissues. Cluster analysis of microarray gene expression demonstrates significant genome wide alterations with major effects in cell-cycle regulation, signal transduction, bile acid and cholesterol metabolism, and control of apoptosis. This study demonstrates a critical proproliferative role for LRH-1 in established colon cancer cell lines. LRH-1 exerts its effects via multiple signaling networks. Our results suggest that selected CRC patients could benefit from LRH-1 inhibitors.
authors: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Francisco, CA 94143-0136;
authors: James R
authors: JR
authors: Bayrer
authors: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2517; and.
authors: Sridevi
authors: S
authors: Mukkamala
authors: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2517; and.
authors: Elena P
authors: EP
authors: Sablin
authors: Department of Genomic Medicine, Houston Methodist Research Institute, Houston, TX 77030.
authors: Paul
authors: P
authors: Webb
authors: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2517; and robert.fletterick@ucsf.edu.
authors: Robert J
authors: RJ
authors: Fletterick
mesh_terms: D018938:Caco-2 Cells; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D019073:HT29 Cells; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: C082631:NR5A2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2
keywords: LRH-1; NR5A2; colorectal cancer; liver receptor homolog 1; nuclear receptor