Fig. 2

Mechanism of HPV-mediated carcinogenesis following oxidative stress and DNA damage. HPV oncoproteins regulate the redox system in different ways. E1/E2 co-expression induces ROS production by decreasing the GSH/GSSG rate (reduced vs oxidized form of GSH) and the activity of SOD1/2 [43]. E6*, an isoform of E6, diminishes the levels of GPx and SOD2 proteins, thereby raising OS levels [12]. E6/E7 oncogenes lead to an increase in ROS levels by inhibiting Nrf2 activity, one of the critical transcription factors contributing to the antioxidant response, and activating Nox2 oxidase [51, 112]. ROS-induced DNA damage, especially DSB facilitates the integration of HPV into the human genome and promotes the overexpression of E6 and E7. E6 oncoprotein induces the apoptosis inhibition and immortalization of host cells through the degradation of p53 and NFX1 proteins. NFX1 is a transcriptional repressor binding to the TERT promoter and represses its expression [113, 114]. On the other hand, E7 oncoprotein promotes uncontrolled proliferation and genomic instability by degradation of pRB and claspin, a primary regulator of the ATR repair pathway [108, 115]. E5 is also capable of inhibiting apoptosis by proteasome-mediated degradation of proapoptotic BAX [116]. Glutathione (GSH), glutathione disulfide (GSSG); superoxide dismutase (SOD); glutathione peroxidase (GPx); nuclear factor erythroid 2–related factor 2 (Nrf2); NADPH oxidase 2 (Nox2); nuclear transcription factor X box-binding protein 1 (NFX1); Telomerase reverse transcriptase (TERT)