Panx1 knockout promotes preneoplastic aberrant crypt foci development in a chemically induced model of mouse colon carcinogenesis

Int J Exp Pathol. 2023 Dec;104(6):304-312. doi: 10.1111/iep.12491. Epub 2023 Aug 18.

Abstract

Colorectal cancer, which is the third leading cause of cancer-related deaths worldwide, is a multistep disease, featuring preneoplastic aberrant crypt foci (ACF) as the early morphological manifestation. The roles of hemichannel-forming transmembrane Pannexin 1 (Panx1) protein have not been investigated in the context of colon carcinogenesis yet, although it has contrasting roles in other cancer types. Thus, this study was conducted to examine the effects of Panx1 knockout (Panx1-/- ) on the early events of chemically induced colon carcinogenesis in mouse. Wild type (WT) and Panx1-/- female C57BL6J mice were submitted to a chemically induced model of colon carcinogenesis by receiving six intraperitoneal administrations of 1,2-dimethylhydrazine (DMH) carcinogen. Animals were euthanized 8 h (week 7) or 30 weeks (week 37) after the last DMH administration in order to evaluate sub-acute colon toxicity outcomes or the burden of ACF, respectively. At week 7, Panx1 genetic ablation increased DMH-induced genotoxicity in peripheral blood cells, malondialdehyde levels in the colon, and apoptosis (cleaved caspase-3) in colonic crypts. Of note, at week 37, Panx1-/- animals showed an increase in aberrant crypts (AC), ACF mean number, and ACF multiplicity (AC per ACF) by 56%, 57% and 20%, respectively. In essence, our findings indicate that Panx1 genetic ablation promotes preneoplastic ACF development during chemically induced mouse colon carcinogenesis, and a protective role of Panx1 is postulated.

Keywords: C57BL/6J mouse; aberrant crypt foci; colon carcinogenesis; dimethylhydrazine.

MeSH terms

  • 1,2-Dimethylhydrazine / adverse effects
  • Aberrant Crypt Foci* / chemically induced
  • Aberrant Crypt Foci* / genetics
  • Animals
  • Carcinogenesis / chemically induced
  • Carcinogenesis / genetics
  • Colon
  • Colonic Neoplasms* / chemically induced
  • Colonic Neoplasms* / genetics
  • Colonic Neoplasms* / metabolism
  • Connexins / genetics
  • Connexins / pharmacology
  • Female
  • Mice
  • Nerve Tissue Proteins / adverse effects
  • Precancerous Conditions* / chemically induced
  • Precancerous Conditions* / genetics

Substances

  • 1,2-Dimethylhydrazine
  • Panx1 protein, mouse
  • Nerve Tissue Proteins
  • Connexins