Estrogenic protection against colorectal cancer development in obesity

项目摘要 散发性结直肠癌(CRC)是一种无家族病史的结直肠癌的亚型，可归因于 各种危险因素，是美国新发结直肠癌病例的大多数(~75%)。肥胖与相关的慢性低度肥胖 炎症是散发性结直肠癌的重要危险因素。尽管女性的肥胖率高于男性， 绝经前女性的结直肠癌发病率低于同龄男性。流行病学研究也表明 绝经后妇女患CRC的风险增加，但接受雌激素替代治疗的妇女有 结直肠癌的发病率大大降低。这些观察表明，促炎脂肪因子和细胞因子与 肥胖是结直肠癌发生的致癌因素，而雌激素是结直肠癌发生的保护因素。然而，雌激素如何 抑制脂肪因子和细胞因子诱导的结直肠癌发病机制尚不清楚。这种知识鸿沟主要是因为 脂肪因子/细胞因子和雌激素在单独的研究中被作为独立的因素进行研究，但它们之间的相互作用 没有在CRC中探索过。此外，尽管癌细胞损害了线粒体代谢功能和 升高的厌氧糖酵解(称为Warburg效应)，最受关注的研究一直集中在研究 潜在的细胞和分子机制，而不是研究涉及的代谢事件。此外，一个合适的 肥胖相关的结直肠癌动物模型需要类似于导致散发性结直肠癌的早期组织病理学特征 在人类身上。在这项建议中，雌激素与脂肪因子瘦素或细胞因子IL-6的相互作用将在体外进行研究。 细胞和活体小鼠模型，以了解雌激素如何通过以下途径防止肥胖环境中的结直肠癌 在细胞、分子、代谢和功能水平上反对瘦素和IL-6的致癌作用。另外， 雌激素受体β(ER-β)选择性激动剂和小干扰β对ER-β的特异性抑制作用 表达将被用来探索雌激素的机制。此外，最初从原代培养获得的细胞系 男性和女性患者的肿瘤和肥胖促进结直肠癌发生的男性和女性小鼠 包括在内，将性视为生物变量。这项研究的结果对于识别特定的性别是非常有价值的 干预预防和治疗肥胖促进的结直肠癌的生物靶点在男性和女性之间是不同的 女人。重要的是，这个项目提供了大量的机会让本科生接触到广泛的 实时定量聚合酶链式反应、流式细胞仪和质谱仪等现代技术，并亲身实践 参与使用体外和体内模型的高质量研究。这些活动将加强研究 迈阿密大学癌症和代谢研究的环境，并促进合作研究机会 涉及俄亥俄州迈阿密大学不同学院不同专业的学生。

Project Summary Sporadic colorectal cancer (CRC), a subtype of CRC without family history but attributed to the presence of various risk factors, is the majority (~75%) of new CRC cases in the US. Obesity and related chronic low-grade inflammation are significant risk factors for sporadic CRC. Although obesity prevalence is higher in women than in men, premenopausal women have lower incidences of CRC than age-matched men. Epidemiology studies have also indicated that postmenopausal women increase their risks for CRC, but women with estrogen replacement therapies have a substantially lower incidence in CRC. These observations suggest proinflammatory adipokines and cytokines associated with obesity as oncogenic factors, whereas estrogen as a protecting factor in CRC development. However, how estrogen suppresses adipokine- and cytokine-induced CRC pathogenesis is unclear. This knowledge gap is mainly because adipokines/cytokines and estrogen have been studied as independent factors in separate studies, but their interaction has not been explored in CRC. Additionally, although cancer cells have impaired mitochondrial metabolic function and elevated anaerobic glycolysis (known as the Warburg effect), most research attention has been focused on studying the underlying cellular and molecular mechanisms, without investigating the metabolic events involved. Further, a suitable obesity-associated CRC animal model is needed to resemble the early histopathologic features leading to sporadic CRC in humans. In this proposal, interaction between estrogen and adipokine leptin or cytokine IL-6 will be studied in in vitro cell and in vivo mouse models to understand how estrogen protects against CRC development in obesity setting, via opposing the oncogenic actions of leptin and IL-6 at cellular, molecular, metabolic, and functional levels. Additionally, estrogen receptor β (ERβ) selective agonist and small interfering RNA transfection to ERβ that specifically reduces ERβ expression will be used to explore estrogenic mechanism. Furthermore, cell lines originally obtained from primary tumors of male and female patients and male and female mice with obesity-promoted colorectal tumorigenesis will be included, considering sex as a biological variable. Findings of this study is invaluable for identifying sex-specific biological targets for intervention to prevent and treat obesity-promoted CRC that would be different between men and women. Importantly, this project provides plentiful opportunities to expose undergraduate students to a broad range of modern techniques such as quantitative real-time PCR, flow cytometry and mass spectrometry, and have hands-on participation in high-quality research using both in vitro and in vivo models. These activities will strengthen research environment in cancer and metabolic research at Miami University, and facilitate collaborative research opportunities involving students of different majors from different colleges at Miami University Ohio.