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

Oxid Med Cell Longev. 2020 Oct 9:2020:6352876. doi: 10.1155/2020/6352876. eCollection 2020.

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.

MeSH terms

  • Autophagy / drug effects
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / drug effects*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Methylnitronitrosoguanidine / pharmacology*
  • NF-E2-Related Factor 2 / metabolism
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / metabolism*
  • Oxidative Stress / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Sequestosome-1 Protein / antagonists & inhibitors
  • Sequestosome-1 Protein / genetics
  • Sequestosome-1 Protein / metabolism
  • Signal Transduction / drug effects*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • DNA-Binding Proteins
  • E6 protein, Human papillomavirus type 18
  • E7 protein, Human papillomavirus type 18
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Oncogene Proteins, Viral
  • RNA, Small Interfering
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Methylnitronitrosoguanidine
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases