title: Pigment Epithelium-Derived Factor (PEDF) Inhibits Wnt/β-catenin Signaling in the Liver.
abstract: 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.
  
  
  
  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).
  
  
  
  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 andβ-catenin, and a PEDF 34-mer peptide decreased LRP6 activation andβ-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.
  
  
  
  PEDF is an endogenous inhibitor of Wnt/β-catenin signaling in the liver.
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut ; VA CT Healthcare System, West Haven, Connecticut.
authors.forename: Petr
authors.initials: P
authors.lastname: Protiva
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Gong
authors.affiliation: VA CT Healthcare System, West Haven, Connecticut.
authors.forename: Bharath
authors.initials: B
authors.lastname: Sreekumar
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, St. Louis, Missouri.
authors.forename: Richard
authors.initials: R
authors.lastname: Torres
authors.affiliation: VA CT Healthcare System, West Haven, Connecticut.
authors.forename: Xuchen
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Belinsky
authors.affiliation: Department of Pathology, St. Louis University School of Medicine, St. Louis, Missouri.
authors.forename: Mona
authors.initials: M
authors.lastname: Cornwell
authors.affiliation: Department of Pathology, St. Louis University School of Medicine, St. Louis, Missouri.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Crawford
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Iwakiri
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut ; VA CT Healthcare System, West Haven, Connecticut.
authors.forename: Chuhan
authors.initials: C
authors.lastname: Chung
keywords: Extracellular Matrix; PEDF; Wnt/β-Catenin