Estrogenic protection against colorectal cancer development in obesity

项目摘要 散发性结直肠癌（CRC）是一种没有家族史的CRC亚型， 各种风险因素，是美国新发CRC病例的大多数（约75%）。肥胖及相关慢性低度 炎症是散发性CRC重要危险因素。虽然女性的肥胖率高于男性， 绝经前女性的CRC发病率低于同龄男性。流行病学研究也表明 绝经后妇女患结直肠癌的风险增加，但接受雌激素替代疗法的妇女 大大降低CRC的发病率。这些观察结果表明，促炎脂肪因子和细胞因子相关 肥胖是致癌因素，而雌激素是CRC发展的保护因素。然而，雌激素 抑制脂肪因子和精氨酸诱导的CRC发病机制尚不清楚。这种知识差距主要是因为 脂肪因子/细胞因子和雌激素在单独的研究中作为独立的因素进行了研究，但它们的相互作用 在CRC中未进行探索。此外，尽管癌细胞具有受损的线粒体代谢功能， 升高的无氧糖酵解（称为瓦尔堡效应），大多数研究注意力都集中在研究 潜在的细胞和分子机制，而不调查所涉及的代谢事件。此外，合适的 需要肥胖相关的CRC动物模型来模拟导致散发性CRC的早期组织病理学特征 在人类身上。本研究拟在体外研究雌激素与脂肪因子瘦素或细胞因子IL-6的相互作用 细胞和体内小鼠模型，以了解雌激素如何在肥胖背景下保护CRC的发展，通过 在细胞、分子、代谢和功能水平上对抗瘦素和IL-6的致癌作用。此外，本发明还 雌激素受体β（ER β）选择性激动剂和特异性降低ER β的ER β小干扰RNA转染 表达将被用于探索雌激素机制。此外，最初从原代获得的细胞系 男性和女性患者的肿瘤以及具有肥胖促进的结肠直肠肿瘤发生的男性和女性小鼠的肿瘤将被 考虑到性别是一个生物学变量。这项研究的结果对于识别性别特异性 干预预防和治疗肥胖促进的CRC的生物学靶点在男性和女性之间是不同的， 妇女重要的是，这个项目提供了大量的机会，让本科生接触到广泛的 定量实时PCR、流式细胞术和质谱法等现代技术，并具有实践经验 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 在迈阿密大学的癌症和代谢研究环境，并促进合作研究的机会 涉及迈阿密大学俄亥俄州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.