Characterization of hERG1 channel role in mouse colorectal carcinogenesis

Cancer Med. 2013 Oct;2(5):583-94. doi: 10.1002/cam4.72. Epub 2013 Jul 22.

Abstract

The human ether-à-go-go-related gene (hERG)1 K(+) channel is upregulated in human colorectal cancer cells and primary samples. In this study, we examined the role of hERG1 in colorectal carcinogenesis using two mouse models: adenomatous polyposis coli (Apc(min/+) ) and azoxymethane (AOM)-treated mice. Colonic polyps of Apc(min/+) mice overexpressed mERG1 and their formation was reverted by the hERG1 blocker E4031. AOM was applied to either hERG1-transgenic (TG) mice, which overexpress hERG1 in the mucosa of the large intestine, or wild-type mice. A significant increase of both mucin-depleted foci and polyps in the colon of hERG1-TG mice was detected. Both the intestine of TG mice and colonic polyps of Apc(min/+) showed an upregulation of phospho-Protein Kinase B (pAkt)/vascular endothelial growth factor (VEGF-A) and an increased angiogenesis, which were reverted by treatment with E4031. On the whole, this article assigns a relevant role to hERG1 in the process of in vivo colorectal carcinogenesis.

Keywords: Apcmin/+ mice; VEGF-A; azoxymethane; colorectal cancer; hERG1 channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli / blood supply
  • Adenomatous Polyposis Coli / metabolism
  • Animals
  • Azoxymethane
  • Carcinogenesis / metabolism*
  • Carcinogens
  • Colorectal Neoplasms / blood supply
  • Colorectal Neoplasms / chemically induced
  • Colorectal Neoplasms / metabolism*
  • Disease Models, Animal
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Ether-A-Go-Go Potassium Channels / biosynthesis
  • Ether-A-Go-Go Potassium Channels / genetics
  • Ether-A-Go-Go Potassium Channels / physiology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intestinal Mucosa / metabolism
  • Intestine, Large / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Piperidines / pharmacology
  • Proto-Oncogene Proteins c-akt / biosynthesis
  • Pyridines / pharmacology
  • Vascular Endothelial Growth Factor A / biosynthesis

Substances

  • Carcinogens
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNH1 protein, human
  • KCNH2 protein, human
  • Neoplasm Proteins
  • Piperidines
  • Pyridines
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • E 4031
  • Proto-Oncogene Proteins c-akt
  • Azoxymethane