Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China.
Oxid Med Cell Longev. 2020 Oct 9;2020:6352876. doi: 10.1155/2020/6352876. eCollection 2020.
N-methyl-N´-nitro-N-nitrosoguanidine is a clear carcinogen, increasing evidence that indicates an etiological role of human papillomavirus in esophageal carcinoma. Studies have reported the synergistic effect on environmental carcinogens and viruses in recent years. On the basis of establishing the malignant transformation model of Het-1A cells induced by synergistic of HPV18 and MNNG, this study was to explore the synergistic carcinogenesis of MNNG and HPV. Our research indicated that HPV&MNNG led to a significant increase in the protein-expression levels of c-Myc, cyclinD1, BCL-2, BAX, E-cadherin, N-cadherin, mTOR, LC3II, and p62, with concomitant decreases in p21 and LC3I. HPV18 and MNNG induced accumulation of p62 and its interaction with KEAP1, which promoted NRF2 nuclear translocation. p62 loss prevents growth and increases autophagy of malignant cells by activating KEAP1/NRF2-dependent antioxidative response. In addition, PI3K and p-AKT were stimulated by HPV&MNNG, and PI3K/AKT/mTOR is positively associated with cell proliferation, migration, invasion, and autophagy during malignant transformation. Taken together, MNNG&HPV regulates autophagy and further accelerates cell appreciation by activating the p62/KEAP1/NRF2 and PI3K/AKT/mTOR pathway. MNNG&HPV may improve Het-1A cell autophagy to contribute to excessive cell proliferation, reduced apoptosis, and protection from oxidative damage, thus accelerating the process of cell malignant transformation and leading to cancerous cells.
N-甲基-N´-亚硝基-N-亚硝胍是一种明确的致癌物质，越来越多的证据表明人乳头瘤病毒（HPV）在食管癌中的病因学作用。近年来的研究报告了环境致癌物质与病毒的协同作用。本研究在建立 HPV18 和 MNNG 协同诱导的 Het-1A 细胞恶性转化模型的基础上，探讨了 MNNG 与 HPV 的协同致癌作用。我们的研究表明，HPV&MNNG 导致 c-Myc、cyclinD1、BCL-2、BAX、E-cadherin、N-cadherin、mTOR、LC3II 和 p62 的蛋白表达水平显著增加，同时 p21 和 LC3I 减少。HPV18 和 MNNG 诱导 p62 及其与 KEAP1 的相互作用增加，促进 NRF2 核转位。p62 的缺失通过激活 KEAP1/NRF2 依赖性抗氧化反应，防止恶性细胞的生长并增加自噬。此外，HPV&MNNG 刺激 PI3K 和 p-AKT，PI3K/AKT/mTOR 与恶性转化过程中的细胞增殖、迁移、侵袭和自噬呈正相关。总之，MNNG&HPV 通过激活 p62/KEAP1/NRF2 和 PI3K/AKT/mTOR 通路调节自噬，进一步加速细胞增殖。MNNG&HPV 可能通过促进自噬来改善 Het-1A 细胞的过度增殖、减少细胞凋亡和氧化损伤保护，从而加速细胞恶性转化过程并导致癌变。
