Targeted Cox2 gene deletion in intestinal epithelial cells decreases tumorigenesis in female, but not male, ApcMin/+ mice

Mol Oncol. 2014 Mar;8(2):169-77. doi: 10.1016/j.molonc.2013.10.009. Epub 2013 Nov 8.


Mice heterozygous for mutations in the adenomatous polyposis coli gene (Apc(+/-) mice) develop intestinal neoplasia. Apc(+/-) tumor formation is thought to be dependent on cyclooxygenase 2 (COX2) expression; both pharmacologic COX2 inhibition and global Cox2 gene deletion reduce the number of intestinal tumors in Apc(+/-) mice. COX2 expression is reported in epithelial cells, fibroblasts, macrophages and endothelial cells of Apc(+/-) mouse polyps. However, the cell type(s) in which COX2 expression is required for Apc(+/-) tumor induction is not known. To address this question, we developed Apc(Min/+) mice in which the Cox2 gene is specifically deleted either in intestinal epithelial cells or in myeloid cells. There is no significant difference in intestinal polyp number between Apc(Min/+) mice with a targeted Cox2 gene deletion in myeloid cells and their control littermate Apc(Min/+) mice. In contrast, Apc(Min/+) mice with a targeted Cox2 deletion in intestinal epithelial cells have reduced intestinal tumorigenesis when compared to their littermate control Apc(Min/+) mice. However, two gender-specific effects are notable. First, female Apc(Min/+) mice developed more intestinal tumors than male Apc(Min/+) mice. Second, targeted intestinal epithelial cell Cox2 deletion decreased tumorigenesis in female, but not in male, Apc(Min/+) mice. Considered in the light of pharmacologic studies and studies with global Cox2 gene knockout mice, our data suggest that (i) intrinsic COX2 expression in intestinal epithelial cells plays a gender-specific role in tumor development in Apc(Min/+) mice, and (ii) COX2 expression in cell type(s) other than intestinal epithelial cells also modulates intestinal tumorigenesis in Apc(Min/+) mice, by a paracrine process.

Keywords: APC; COX2; Cyclooxygenase 2; Gender-specific effect; Mouse intestinal tumors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenomatous Polyposis Coli / enzymology
  • Adenomatous Polyposis Coli / genetics
  • Adenomatous Polyposis Coli / pathology
  • Adenomatous Polyposis Coli Protein* / genetics
  • Adenomatous Polyposis Coli Protein* / metabolism
  • Animals
  • Cyclooxygenase 2* / biosynthesis
  • Cyclooxygenase 2* / genetics
  • Female
  • Gene Deletion*
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic*
  • Intestinal Mucosa* / enzymology
  • Intestinal Mucosa* / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Sex Characteristics*


  • Adenomatous Polyposis Coli Protein
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2