1. Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs
- Author
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Bayrer, James R, Mukkamala, Sridevi, Sablin, Elena P, Webb, Paul, and Fletterick, Robert J
- Subjects
Genetics ,Cancer ,Liver Disease ,Colo-Rectal Cancer ,Digestive Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Caco-2 Cells ,Cell Cycle ,Cell Proliferation ,Colonic Neoplasms ,Gene Expression Regulation ,Neoplastic ,Gene Knockdown Techniques ,Gene Silencing ,HT29 Cells ,Humans ,Oligonucleotide Array Sequence Analysis ,Receptors ,Cytoplasmic and Nuclear ,Reproducibility of Results ,liver receptor homolog 1 ,LRH-1 ,NR5A2 ,nuclear receptor ,colorectal cancer - 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.
- Published
- 2015