Departments of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea.
Departments of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
Biochem Pharmacol. 2019 Jun;164:139-151. doi: 10.1016/j.bcp.2019.04.011. Epub 2019 Apr 11.
Estrogen is known to have a protective effect in colorectal cancer (CRC) development. Previously, we reported the anti-inflammatory and antitumorigenic effects of 17β-estradiol (E2) in azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated male mice. The aim of this study was to investigate whether ovariectomy in a female AOM/DSS mouse model increases colorectal tumorigenesis and whether tumorigenesis is reduced by estrogen supplementation after ovariectomy. Clinical symptoms and histological severity of colitis and the levels of inflammatory mediators were evaluated in the colon of AOM/DSS-treated ovariectomized (OVX) mice. The levels of E2, myeloperoxidase (MPO), and NF-κB-dependent cytokines (interleukin (IL)-1β and IL-6) were measured by ELISA. Furthermore, quantitative real-time (qRT) PCR and Western blot analysis were performed. Ovariectomy did not aggravate AOM/DSS-induced colitis at 2 weeks. At weeks 10 and 16, ovariectomy significantly increased tumor number and incidence rate in only the proximal colon after AOM/DSS treatment (F_AOM/DSS vs OVX_AOM/DSS), and these increases were significantly reduced by E2 supplementation (OVX_AOM/DSS vs OVX_AOM/DSS/E2). However, ovariectomy did not affect CRC development in the distal colon (F_AOM/DSS vs OVX_AOM/DSS). At week 2, E2 administration to AOM/DSS-treated OVX mice attenuated the histological severity of colitis by decreasing the protein and/or mRNA levels of estrogen receptor alpha (ERα) and NF-κB-related mediators (i.e., COX-2, TNF-α, and IL-6) and by enhancing estrogen receptor beta (ERβ) and nuclear Nrf2 protein expression and the mRNA expression of related antioxidant enzyme genes (i.e., HO-1, GCLC, GCLM, and NQO1). Endogenous estrogen in females protects against the development of proximal colon cancer, and exogenous E2 replacement in OVX female mice showed protective effects against AOM/DSS-induced colitis and carcinogenesis. The mechanism could involve modulating ERs-, NF-κB- and Nrf2-mediated pathways.
雌激素被认为对结直肠癌（CRC）的发展具有保护作用。此前，我们报道了 17β-雌二醇（E2）在氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）处理的雄性小鼠中的抗炎和抗肿瘤作用。本研究旨在探讨在雌性 AOM/DSS 小鼠模型中卵巢切除是否会增加结直肠肿瘤发生，以及卵巢切除后雌激素补充是否会减少肿瘤发生。在 AOM/DSS 处理的卵巢切除（OVX）小鼠的结肠中评估了结肠炎的临床症状和组织学严重程度以及炎症介质的水平。通过 ELISA 测量 E2、髓过氧化物酶（MPO）和 NF-κB 依赖性细胞因子（白细胞介素（IL）-1β和 IL-6）的水平。此外，进行了定量实时（qRT）PCR 和 Western blot 分析。卵巢切除在 2 周时并没有加重 AOM/DSS 诱导的结肠炎。在第 10 和 16 周，卵巢切除仅在 AOM/DSS 处理后显著增加近端结肠的肿瘤数量和发生率（F_AOM/DSS 与 OVX_AOM/DSS），而 E2 补充显著降低了这些增加（OVX_AOM/DSS 与 OVX_AOM/DSS/E2）。然而，卵巢切除对远端结肠的 CRC 发展没有影响（F_AOM/DSS 与 OVX_AOM/DSS）。在第 2 周，给予 AOM/DSS 处理的 OVX 小鼠 E2 可通过降低雌激素受体α（ERα）和 NF-κB 相关介质（即 COX-2、TNF-α和 IL-6）的蛋白和/或 mRNA 水平，并通过增强雌激素受体β（ERβ）和核 Nrf2 蛋白表达以及相关抗氧化酶基因（即 HO-1、GCLC、GCLM 和 NQO1）的 mRNA 表达来减轻结肠炎的组织学严重程度。女性体内的内源性雌激素可预防近端结肠癌的发生，而 OVX 雌性小鼠中 E2 的外源性替代对 AOM/DSS 诱导的结肠炎和癌变具有保护作用。其机制可能涉及调节 ERs、NF-κB 和 Nrf2 介导的途径。
