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Pigment Epithelium-Derived Factor (PEDF) Inhibits Wnt/β-catenin Signaling in the Liver

BACKGROUND & AIMS: Pigment epithelium-derived factor (PEDF) is a secretory protein that inhibits multiple tumor types. PEDF inhibits the Wnt coreceptor, low-density lipoprotein receptor-related protein 6 (LRP6), in the eye, but whether the tumor-suppressive properties of PEDF occur in organs suc...

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Autores principales: Protiva, Petr, Gong, Jingjing, Sreekumar, Bharath, Torres, Richard, Zhang, Xuchen, Belinsky, Glenn S., Cornwell, Mona, Crawford, Susan E., Iwakiri, Yasuko, Chung, Chuhan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604042/
https://www.ncbi.nlm.nih.gov/pubmed/26473164
http://dx.doi.org/10.1016/j.jcmgh.2015.06.006
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author Protiva, Petr
Gong, Jingjing
Sreekumar, Bharath
Torres, Richard
Zhang, Xuchen
Belinsky, Glenn S.
Cornwell, Mona
Crawford, Susan E.
Iwakiri, Yasuko
Chung, Chuhan
author_facet Protiva, Petr
Gong, Jingjing
Sreekumar, Bharath
Torres, Richard
Zhang, Xuchen
Belinsky, Glenn S.
Cornwell, Mona
Crawford, Susan E.
Iwakiri, Yasuko
Chung, Chuhan
author_sort Protiva, Petr
collection PubMed
description BACKGROUND & AIMS: Pigment epithelium-derived factor (PEDF) is a secretory protein that inhibits multiple tumor types. PEDF inhibits the Wnt coreceptor, low-density lipoprotein receptor-related protein 6 (LRP6), in the eye, but whether the tumor-suppressive properties of PEDF occur in organs such as the liver is unknown. METHODS: Wnt-dependent regulation of PEDF was assessed in the absence and presence of the Wnt coreceptor LRP6. Whole genome expression analysis was performed on PEDF knockout (KO) and control livers (7 months). Interrogation of Wnt/β-catenin signaling was performed in whole livers and human hepatocellular carcinoma (HCC) cell lines after RNA interference of PEDF and restoration of a PEDF-derived peptide. Western diet feeding for 6 to 8 months was used to evaluate whether the absence of PEDF was permissive for HCC formation (n = 12/group). RESULTS: PEDF levels increased in response to canonical Wnt3a in an LRP6-dependent manner but were suppressed by noncanonical Wnt5a protein in an LRP6-independent manner. Gene set enrichment analysis (GSEA) of PEDF KO livers revealed induction of pathways associated with experimental and human HCC and a transcriptional profile characterized by Wnt/β-catenin activation. Enhanced Wnt/β-catenin signaling occurred in KO livers, and PEDF delivery in vivo reduced LRP6 activation. In human HCC cells, RNA interference of PEDF led to increased levels of activated LRP6 and β-catenin, and a PEDF 34-mer peptide decreased LRP6 activation and β-catenin signaling, and reduced Wnt target genes. PEDF KO mice fed a Western diet developed sporadic well-differentiated HCC. Human HCC specimens demonstrated decreased PEDF staining compared with hepatocytes. CONCLUSIONS: PEDF is an endogenous inhibitor of Wnt/β-catenin signaling in the liver.
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spelling pubmed-46040422015-10-13 Pigment Epithelium-Derived Factor (PEDF) Inhibits Wnt/β-catenin Signaling in the Liver Protiva, Petr Gong, Jingjing Sreekumar, Bharath Torres, Richard Zhang, Xuchen Belinsky, Glenn S. Cornwell, Mona Crawford, Susan E. Iwakiri, Yasuko Chung, Chuhan Cell Mol Gastroenterol Hepatol Original Research BACKGROUND & AIMS: Pigment epithelium-derived factor (PEDF) is a secretory protein that inhibits multiple tumor types. PEDF inhibits the Wnt coreceptor, low-density lipoprotein receptor-related protein 6 (LRP6), in the eye, but whether the tumor-suppressive properties of PEDF occur in organs such as the liver is unknown. METHODS: Wnt-dependent regulation of PEDF was assessed in the absence and presence of the Wnt coreceptor LRP6. Whole genome expression analysis was performed on PEDF knockout (KO) and control livers (7 months). Interrogation of Wnt/β-catenin signaling was performed in whole livers and human hepatocellular carcinoma (HCC) cell lines after RNA interference of PEDF and restoration of a PEDF-derived peptide. Western diet feeding for 6 to 8 months was used to evaluate whether the absence of PEDF was permissive for HCC formation (n = 12/group). RESULTS: PEDF levels increased in response to canonical Wnt3a in an LRP6-dependent manner but were suppressed by noncanonical Wnt5a protein in an LRP6-independent manner. Gene set enrichment analysis (GSEA) of PEDF KO livers revealed induction of pathways associated with experimental and human HCC and a transcriptional profile characterized by Wnt/β-catenin activation. Enhanced Wnt/β-catenin signaling occurred in KO livers, and PEDF delivery in vivo reduced LRP6 activation. In human HCC cells, RNA interference of PEDF led to increased levels of activated LRP6 and β-catenin, and a PEDF 34-mer peptide decreased LRP6 activation and β-catenin signaling, and reduced Wnt target genes. PEDF KO mice fed a Western diet developed sporadic well-differentiated HCC. Human HCC specimens demonstrated decreased PEDF staining compared with hepatocytes. CONCLUSIONS: PEDF is an endogenous inhibitor of Wnt/β-catenin signaling in the liver. Elsevier 2015-07-04 /pmc/articles/PMC4604042/ /pubmed/26473164 http://dx.doi.org/10.1016/j.jcmgh.2015.06.006 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Protiva, Petr
Gong, Jingjing
Sreekumar, Bharath
Torres, Richard
Zhang, Xuchen
Belinsky, Glenn S.
Cornwell, Mona
Crawford, Susan E.
Iwakiri, Yasuko
Chung, Chuhan
Pigment Epithelium-Derived Factor (PEDF) Inhibits Wnt/β-catenin Signaling in the Liver
title Pigment Epithelium-Derived Factor (PEDF) Inhibits Wnt/β-catenin Signaling in the Liver
title_full Pigment Epithelium-Derived Factor (PEDF) Inhibits Wnt/β-catenin Signaling in the Liver
title_fullStr Pigment Epithelium-Derived Factor (PEDF) Inhibits Wnt/β-catenin Signaling in the Liver
title_full_unstemmed Pigment Epithelium-Derived Factor (PEDF) Inhibits Wnt/β-catenin Signaling in the Liver
title_short Pigment Epithelium-Derived Factor (PEDF) Inhibits Wnt/β-catenin Signaling in the Liver
title_sort pigment epithelium-derived factor (pedf) inhibits wnt/β-catenin signaling in the liver
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604042/
https://www.ncbi.nlm.nih.gov/pubmed/26473164
http://dx.doi.org/10.1016/j.jcmgh.2015.06.006
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