Cancer Res Treat.  2019 Apr;51(2):632-648. 10.4143/crt.2018.060.

Effect of Estradiol in an Azoxymethane/Dextran Sulfate Sodium-Treated Mouse Model of Colorectal Cancer: Implication for Sex Difference in Colorectal Cancer Development

Affiliations
  • 1Seoul National University College of Medicine, Seoul, Korea.
  • 2Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea. nayoungkim49@empas.com
  • 3Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.
  • 4Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, Korea.
  • 5Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea.

Abstract

PURPOSE
This study demonstrates that estradiol downregulates inflammation and inhibits colorectal cancer (CRC) development in azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model.
MATERIALS AND METHODS
AOM/DSS-treated male and female mice were sacrificed at weeks 2, 10, and 16, to assess estrogen effects on colitis and carcinogenesis. Macroscopic and histologic severity of colitis and Western blot and quantitative real-time polymerase chain reaction were evaluated, to measure inflammatory mediators and cytokines.
RESULTS
Compared with AOM/DSS-treated male mice (M-AOM/DSS group), AOM/DSS-treated male mice with estradiol administration (M-AOM/DSS+estr group) displayed at week 2 significantly decreased severity of colitis. At weeks 10 and 16, AOM/DSS-treated female mice (F-AOM/DSS group) and the M-AOM/DSS+estr group showed significantly lower tumor multiplicity compared with the M-AOM/DSS group. At week 2, F-AOM/DSS group had a lower level of nuclear factor-κB (NF-κB) expression and higher level of nuclear factor erythroid 2-related factor 2 (Nrf2) expression, compared to the M-AOM/DSS group. At week 2, expression levels of NF-κB and its related mediators decreased in the M-AOM/DSS+estr group, while levels of Nrf2 and Nrf2-related anti-oxidant enzymes increased. In addition, estradiol significantly increased Nod-like receptor protein 3 (NLRP3) inflammasome expressions in AOM/DSS-treated male mice. In contrast, at weeks 10 and 16, Nrf2 and its-related anti-oxidant enzymes and NLRP3 inflammasome were highly expressed in M-AOM/DSS group and in F-AOM/DSS group, who developed cancer.
CONCLUSION
The data suggest that estradiol inhibits the initiation of CRC by regulating Nrf2-related pathways. Moreover, these imply the dual role of Nrf2 and NLRP3 inflammasome, including promotion of tumor progression upon tumor initiation.

Keyword

Colorectal Neoplasms; AOM/DSS mouse model; Estradiol; NF-kappa B; NF-E2-Related Factor 2; Nod-like receptor protein 3 inflammasome; Mouse

MeSH Terms

Animals
Blotting, Western
Carcinogenesis
Colitis
Colorectal Neoplasms*
Cytokines
Estradiol*
Estrogens
Female
Humans
Inflammasomes
Inflammation
Male
Mice*
NF-E2-Related Factor 2
NF-kappa B
Real-Time Polymerase Chain Reaction
Sex Characteristics*
Sodium
Cytokines
Estradiol
Estrogens
Inflammasomes
NF-E2-Related Factor 2
NF-kappa B
Sodium
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