Estrogenic protection against colorectal cancer development in obesity

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.