Su Po-Hsuan, Hsu Yao-Wen, Huang Rui-Lan, Weng Yu-Chun, Wang Hui-Chen, Chen Yu-Chih, Tsai Yueh-Ju, Yuan Chiou-Chung, Lai Hung-Cheng
Translational Epigenetics Center, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
Oncotarget. 2017 Jun 6;8(39):65281-65291. doi: 10.18632/oncotarget.18370. eCollection 2017 Sep 12.
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 . Whole-genome methylation analysis showed , , , , and were hypermethylated in cells. The hypermethylation , , , and was confirmed in cervical scrapings from invasive cancer, but not in CIN3/CIS, CIN2 and CIN1 (=0.019, 0.023, 0.023 and 0.027 respectively), suggesting the role in the transition from 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.
表观遗传失调在宫颈癌发展过程中具有重要作用，但其潜在机制在很大程度上仍不清楚。越来越多的证据表明，DNA甲基化对微环境因素的变化敏感，如慢性炎症宫颈中的一氧化氮（NO）。然而，NO在癌症中的表观基因组效应尚未得到研究。在本研究中，我们探讨了氧化亚氮应激在人乳头瘤病毒（HPV）永生化癌前细胞中的甲基化组效应。长期暴露于NO促进了恶性表型的获得，如细胞生长、迁移、侵袭和非锚定依赖性生长。表观遗传分析证实了……的高甲基化。全基因组甲基化分析显示，……基因在细胞中发生了高甲基化。在浸润性癌的宫颈刮片中证实了……的高甲基化，但在CIN3/CIS、CIN2和CIN1中未得到证实（P值分别为0.019、0.023、0.023和0.027），这表明其在从……向浸润过程转变中的作用。我们的结果表明，氧化亚氮应激会导致HPV感染细胞发生表观遗传变化。研究持续性HPV感染中的这些甲基化变化可能有助于识别用于宫颈癌筛查，尤其是癌前病变筛查的新型DNA甲基化生物标志物。
