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Research Article

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

Cindy Benod, Maia V. Vinogradova, Natalia Jouravel, Grace E. Kim, Robert J. Fletterick, and Elena P. Sablin
PNAS first published September 26, 2011; https://doi.org/10.1073/pnas.1112047108
Cindy Benod
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Maia V. Vinogradova
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Natalia Jouravel
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Grace E. Kim
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Robert J. Fletterick
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  • For correspondence: Robert.Fletterick@ucsf.edu
Elena P. Sablin
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  1. Contributed by Robert J. Fletterick, August 18, 2011 (sent for review May 23, 2011)

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Abstract

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 ductal 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.

  • protein target
  • gene regulation

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: Robert.Fletterick{at}ucsf.edu.
  • Author contributions: R.J.F. and E.P.S. designed research; C.B., M.V.V., and N.J. performed research; C.B. and M.V.V. contributed new reagents/analytic tools; C.B., M.V.V., N.J., G.E.K., R.J.F., and E.P.S. analyzed data; G.E.K. interpreted immunohistochemistry pathology data; and C.B., M.V.V., R.J.F., and E.P.S. wrote the paper.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1112047108/-/DCSupplemental.

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Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation
Cindy Benod, Maia V. Vinogradova, Natalia Jouravel, Grace E. Kim, Robert J. Fletterick, Elena P. Sablin
Proceedings of the National Academy of Sciences Sep 2011, DOI: 10.1073/pnas.1112047108

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Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation
Cindy Benod, Maia V. Vinogradova, Natalia Jouravel, Grace E. Kim, Robert J. Fletterick, Elena P. Sablin
Proceedings of the National Academy of Sciences Sep 2011, DOI: 10.1073/pnas.1112047108
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