Synergistic Carcinogenesis of HPV18 and MNNG in Het-1A Cells through p62-KEAP1-NRF2 and PI3K/AKT/mTOR Pathway.

Ying Zhang,Yue Ma,Hu Zhang,Lihong Yin,Chao Zhao,Yuepu Pu

doi:10.1155/2020/6352876

Abstract

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.

Highlights

Esophageal cancer (EC) is the fourth cause of death of malignant tumors in China and the seventh most common malignant tumor in the world [1], posing a serious threat to human health
Our preliminary research indicated a high incidence of human papillomavirus (HPV) infection in the esophageal carcinoma specimens from this area [20]
The c-Myc expression of HPV+MNNG group and MNNG group increased with the infection passage and increased significantly in HPV transfect cells

Summary

Introduction

Esophageal cancer (EC) is the fourth cause of death of malignant tumors in China and the seventh most common malignant tumor in the world [1], posing a serious threat to human health. There are complex interactions between internal and external causes of the development of esophageal cancer. Syrjanen et al [6] firstly reported the characteristic changes of human papillomavirus (HPV) infection in esophageal cancer tissues since 1982, and researchers turn to pay extensive attention to the correlation between esophageal cancer and HPV infection. In the process of exploiting its complex etiology, more evidence shows that HPV infection is related to the occurrence [7] and development of esophageal cancer [8], and HPV may be an important biological factor leading to esophageal cancer

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