Extracellular calcium-sensing receptor/PTH knockout mice colons have increased Wnt/β-catenin signaling, reduced non-canonical Wnt signaling, and increased susceptibility to azoxymethane-induced aberrant crypt foci

Research output: Contribution to journalArticle (Academic Journal)peer-review

33 Citations (Scopus)

Abstract

Epidemiological evidence suggests increased dietary calcium and dairy products reduce the onset of colon cancer. To understand a role of the colonic extracellular calcium-sensing receptor (CaSR) in calcium-mediated chemoprevention of colon cancer, we induced formation of aberrant crypt foci (ACF) caused by azoxymethane (AOM) injection in 'rescued' CaSR-/PTH- (C-/P-) double knockout colons compared with colons from control CaSR+/PTH+ (C+/P+) mice. C-/P- colonic epithelia had increased Wnt/β-catenin signaling as evidenced by 3-8-fold increases in Wnt3a, CyclinD1, and MMP-7 proteins compared with C+/P+ colonic epithelia. The C-/P- colonic epithelia had reduced Wnt5a and Ror2, and a three-fold increase in TNFR1 compared with C+/P+ epithelia. The C-/P- colons and small intestine had extensive neutrophil infiltration with myeloperoxidase (MPO) levels 18-fold higher then C+/P+ small intestine and colon. Saline-injected C-/P- colons had the same number of ACF/cm(2) as C+/P+ colons, which were injected with AOM. However, there were eight times more ACF/cm(2) in the C-/P- injected with AOM compared with C+/P+ colons, which received AOM. Together our results suggest both inflammation and Wnt/β-catenin signaling are increased in the epithelia of 'rescued' CaSR/PTH double knockout colons, and the capacity for non-canonical Wnt signaling through Wnt5a/Ror2 engagement is reduced. The loss of the colonic CaSR increased the number of ACF/cm(2) in response to AOM injection, suggesting colonic CaSR may mediate the chemoprotective effect of increased dietary calcium against colorectal cancer observed in humans.

Original languageEnglish
Pages (from-to)520-7
Number of pages8
JournalLaboratory Investigation
Volume93
Issue number5
DOIs
Publication statusPublished - May 2013

Keywords

  • Aberrant Crypt Foci
  • Animals
  • Azoxymethane
  • Blotting, Western
  • Colon
  • Cyclin D1
  • Genetic Predisposition to Disease
  • Intestine, Small
  • Matrix Metalloproteinase 7
  • Mice
  • Mice, Knockout
  • Parathyroid Hormone
  • Peroxidase
  • Receptor Tyrosine Kinase-like Orphan Receptors
  • Receptors, Calcium-Sensing
  • Receptors, Tumor Necrosis Factor, Type I
  • Signal Transduction
  • Wnt Proteins
  • Wnt3A Protein
  • beta Catenin

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