Distinct roles of histamine H1- and H2-receptor signaling pathways in inflammation-associated colonic tumorigenesis

We further demonstrated that administration of a histamine H1-receptor antagonist suppressed tumorigenesis, while administration of histamine H2-receptor antagonist significantly increased both tumor number and size

Zhongcheng Shi; Robert S. Fultz; Melinda A. Engevik; Chunxu Gao; Anne Hall; Angela Major; Yuko Mori-Akiyama; James Versalovic

2018

Scholarcy highlights

  • Discovered more than 100 years ago, histamine is an important signaling compound affecting a variety of biological processes, including neuronal activity, endothelial permeability, vascular tone and gastric acid secretion, inflammation, allergy, and development of cancer
  • Histologic differences were not observed in the adenomas among different groups, mice that received histamine-producing L. reuteri had fewer dysplastic lesions, indicating that bacterial histamine from the intestinal microbiome is capable of suppressing inflammation-associated tumorigenesis and dysplasia in ApcMin/ϩ mice
  • To explore the roles of H1R and H2R signaling pathways in human colorectal cancer, we examined if elevated expression of HRH2) vs. H1R or HRH2 in CRC tissue specimens were associated with CRC patient outcomes using the R2 Platform
  • In human colon cancer-derived cells and immune cells, H2R signaling counteracted H1R-mediated mitogen-activated protein kinases activation, and MAPK activation contributes to the development of chronic intestinal inflammation and cancer
  • These findings in human cell culture and mouse models are consistent with patient outcomes based on gene expression profiles in human CRC, whereby elevated HRH1 and reduced HRH2 gene expression were correlated with worse patient outcomes
  • The data suggest that the ratio of HRH2/HRH1 expression in human tissue could represent a new prognostic biomarker for Inflammatory bowel disease and CRC and such insight could point the way to new disease preventive and therapeutic strategies that rely on histamine-receptor signaling
  • In Inflammatory bowel disease, activation of p38 signaling results in elevated TNF expression and in mouse models of colon cancer; inactivation of p38 mitogen-activated protein kinases signaling significantly suppressed colon tumor development

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