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Proc Natl Acad Sci U S A. 2015 Feb 24;112(8):2467-72. doi: 10.1073/pnas.1500978112. Epub 2015 Feb 9.

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs.

Author information

1
Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Francisco, CA 94143-0136;
2
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2517; and.
3
Department of Genomic Medicine, Houston Methodist Research Institute, Houston, TX 77030.
4
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2517; and robert.fletterick@ucsf.edu.

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.

KEYWORDS:

LRH-1; NR5A2; colorectal cancer; liver receptor homolog 1; nuclear receptor

PMID:
25675535
PMCID:
PMC4345603
DOI:
10.1073/pnas.1500978112
[Indexed for MEDLINE]
Free PMC Article

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