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Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a dual role in carcinogenesis. We previously reported that Nrf2 deficiency enhances the anti-tumorigenic effect of 17β-estradiol (E2) in an azoxymethane (AOM)/dextran sodium sulfate (DSS) model of colitis-associated cancer (CAC). Herein, we aimed to determine a possible explanation for our recent work and investigated the immune microenvironment represented by programmed death-ligand 1 (PD-L1) expression. One week after the AOM injection, mice were administered with DSS in drinking water for seven days; daily E2 injections were intraperitoneally administered during this period. The mice were sacrificed 16 weeks after AOM injection and analyzed for PD-L1 expression in the distal colon tissues using Western blotting and immunohistochemistry (IHC). Based on Western blotting results, PD-L1 expression was reduced in Nrf2 knockout (KO) female and E2-treated male mice when compared with their wild-type counterparts, following AOM/DSS treatment; this supports the association of PD-L1 expression with tumor progression. Additionally, this finding was in good agreement with the IHC results for PD-L1. Furthermore, we observed that PD-L1 is predominantly expressed in stromal cells rather than on epithelial cells in the colon. Western blotting revealed that PD-L1 expression in the colon positively correlates with expressions of inducible nitric oxide synthase (iNOS) (male, P = 0.002; female, P <0.001) and cyclooxygenase-2 (COX-2) (male, P <0.001; female, P <0.001). Collectively, our findings indicate that estrogen ameliorates the immune microenvironment represented by PD-L1 expression and enhances its effect in the absence of Nrf2.

Affiliations

Changhee Kang  1 , Chin-Hee Song  1 , Nayoung Kim  1   2 , Ryoung Hee Nam  1 , Soo In Choi  1 , Jeong Eun Yu  1 , Heewon Nho  1 , Jin A Choi  1 , Jin Won Kim  1 , Hee Young Na  3 , Ha-Na Lee  4 , Young-Joon Surh  5   6
1 Departments of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.
2 Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
3 Departments of Pathology, Seoul National University Bundang Hospital, Seongnam, South Korea.
4 Laboratory of Immunology, Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
5 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.
6 Cancer Research Institute, Seoul National University, Seoul, South Korea.