Shuwei Li1, Yehua Chen1, Lisheng Xie2, Yixuan Meng3, Lingjun Zhu4, Haiyan Chu3, Dongying Gu5, Zhengdong Zhang3, Mulong Du6, Meilin Wang7. 1. State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China; Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. 2. Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Infection Control, Zhongshan Hospital Qingpu Branch, Fudan University, Shanghai, China. 3. Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. 4. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 5. Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. 6. Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China. 7. State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China; Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. Electronic address: mwang@njmu.edu.cn.
Abstract
OBJECTIVE: The different incidence of colorectal cancer between the sexes suggests that sex hormones may be involved in the susceptibility to colorectal cancer. The association between sex hormones and genetic variants in hormone metabolic pathways and the colorectal cancer risk remains unclear. METHODS: We detected sex hormone levels in plasma from colorectal cancer patients and controls in males by ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). We evaluated the clinical significance of sex hormones on colorectal cancer diagnosis with the area under the receiver operating characteristic curve (AUC). The role of genetic variants in hormone metabolic pathways in the colorectal cancer risk was assessed by a logistic regression model. The biological functions were detected by luciferase reporter assays and cell behavior experiments. RESULTS: We found that 2-methoxyestrone (2-MeO-E1) was highly expressed in cases (PFDR = 3.48 × 10-19). The expression of 2-MeO-E1 in plasma showed improved accuracy for predicting colorectal cancer (AUC = 0.88). In the 2-MeO-E1 metabolic pathway, rs165599 in COMT was significantly associated with an increased risk of colorectal cancer (P = 0.009). Mechanistically, we found that the rs165599 G allele could decrease the binding ability of miR-22-3p to the COMT 3'-UTR. Furthermore, knockdown of COMT inhibited cell proliferation, induced cell apoptosis and arrested the cell cycle in the G1 phase. CONCLUSION: This is the first study to show that 2-MeO-E1 and a genetic variant in COMT contribute to the susceptibility to colorectal cancer. These results shed light on the different incidence of colorectal cancer between the sexes.
OBJECTIVE: The different incidence of colorectal cancer between the sexes suggests that sex hormones may be involved in the susceptibility to colorectal cancer. The association between sex hormones and genetic variants in hormone metabolic pathways and the colorectal cancer risk remains unclear. METHODS: We detected sex hormone levels in plasma from colorectal cancerpatients and controls in males by ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). We evaluated the clinical significance of sex hormones on colorectal cancer diagnosis with the area under the receiver operating characteristic curve (AUC). The role of genetic variants in hormone metabolic pathways in the colorectal cancer risk was assessed by a logistic regression model. The biological functions were detected by luciferase reporter assays and cell behavior experiments. RESULTS: We found that 2-methoxyestrone (2-MeO-E1) was highly expressed in cases (PFDR = 3.48 × 10-19). The expression of 2-MeO-E1 in plasma showed improved accuracy for predicting colorectal cancer (AUC = 0.88). In the 2-MeO-E1 metabolic pathway, rs165599 in COMT was significantly associated with an increased risk of colorectal cancer (P = 0.009). Mechanistically, we found that the rs165599 G allele could decrease the binding ability of miR-22-3p to the COMT 3'-UTR. Furthermore, knockdown of COMT inhibited cell proliferation, induced cell apoptosis and arrested the cell cycle in the G1 phase. CONCLUSION: This is the first study to show that 2-MeO-E1 and a genetic variant in COMT contribute to the susceptibility to colorectal cancer. These results shed light on the different incidence of colorectal cancer between the sexes.
Authors: Muktar Ahmed; Ville-Petteri Mäkinen; Anwar Mulugeta; Jisu Shin; Terry Boyle; Elina Hyppönen; Sang Hong Lee Journal: Commun Biol Date: 2022-06-21