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

James R. Bayrer, Sridevi Mukkamala, Elena P. Sablin, Paul Webb, Robert J. Fletterick

Research output: Contribution to journalArticle

35 Scopus citations

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 cellcycle 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.

Original languageEnglish (US)
Pages (from-to)2467-2472
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number8
DOIs
StatePublished - Mar 18 2015

Keywords

  • Colorectal cancer
  • LRH-1
  • Liver receptor homolog 1
  • NR5A2
  • Nuclear receptor

ASJC Scopus subject areas

  • General

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