Methylomics of nitroxidative stress on precancerous cells reveals DNA methylation alteration at the transition from in situ to invasive cervical cancer
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Po-Hsuan Su1,2, Yao-Wen Hsu3, Rui-Lan Huang2, Yu-Chun Weng1,2, Hui-Chen Wang4, Yu-Chih Chen5, Yueh-Ju Tsai2, Chiou-Chung Yuan2 and Hung-Cheng Lai1,2,4,6,7
1Translational Epigenetics Center, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
2Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
3Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
4Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
5Division of Research and Analysis, Food and Drug Administration, Ministry of Health and Welfare, Taipei, Taiwan
6Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China
7Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China
Hung-Cheng Lai, email: [email protected], [email protected]
Keywords: chronic inflammation, nitric oxide, nitroxidative stress, gene specific hypermethylation
Received: December 20, 2016 Accepted: April 26, 2017 Published: June 06, 2017
Epigenetic dysregulation is important in cervical cancer development, but the underlying mechanism is largely unknown. Increasing evidence indicates that DNA methylation is sensitive to changes in microenvironmental factors, such as nitric oxide (NO) in the chronic inflammatory cervix. However, the epigenomic effects of NO in cancer have not been investigated. In this study, we explored the methylomic effects of nitroxidative stress in HPV-immortalized precancerous cells. Chronic NO exposure promoted the acquisition of malignant phenotypes such as cell growth, migration, invasion, and anchorage-independent growth. Epigenetic analysis confirmed hypermethylation of PTPRR. Whole-genome methylation analysis showed BOLA2B, FGF8, HSPA6, LYPD2, and SHE were hypermethylated in cells. The hypermethylation BOLA2B, FGF8, HSPA6, and SHE was confirmed in cervical scrapings from invasive cancer, but not in CIN3/CIS, CIN2 and CIN1 (p=0.019, 0.023, 0.023 and 0.027 respectively), suggesting the role in the transition from in situ to invasive process. Our results reveal that nitroxidative stress causes epigenetic changes in HPV-infected cells. Investigation of these methylation changes in persistent HPV infection may help identify new biomarkers of DNA methylation for cervical cancer screening, especially for precancerous lesions.
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