E5 Oncoprotein: A Key Player in Human Papillomavirus-Positive Head and Neck Cancer Pathogenesis and Therapy Resistance

Abstract

Head and neck cancer (HNC) is the sixth most prevalent type of cancer worldwide and is associated with low five-year survival rates. Alcoholism and smoking are the main risk factors associated with the development of head and neck cancer (HNC). However, Human Papillomavirus (HPV) infection has been reported as a significant risk factor, particularly for the oropharyngeal subset. In these cases, patients with HPV-positive HNC exhibit a better clinical prognosis; however, resistance to chemotherapy has been frequently reported. The carcinogenic activity of HPV is related to the viral oncoproteins E5, E6, and E7. E5 has been associated with immune evasion mechanisms and modulation of the tumor microenvironment, which appears to be linked to the virus's resistance to chemotherapeutic treatments. Here, we review the potential of HPV E5 in targeted therapy for HNC and discuss relevant data regarding the activity of this oncoprotein in head and neck carcinogenesis.

Keywords: HNC; human papillomavirus; immune evasion; oncoprotein; tumor microenvironment.

Figure 1

Structure and genome of HPV16 E5 In illustration (A), the three hydrophobic transmembrane domains of the HPV16 E5α protein are depicted illustratively. In the adjacent diagram (B), the complete HPV16 genome is shown, along with a specific splicing event containing the E5 gene and the truncated initial region of E6 (E6*).

Figure 2

Impact of HPV E5 Oncoprotein on Immune Evasion and Modulation of Cellular Pathways Critical to Oncogenesis. This figure illustrates the multifaceted impact of the HPV E5 oncoprotein on host cells. E5 contributes to immune evasion by limiting antigen presentation through MHC I retention on the host cell, increasing PD-L1 expression, and inhibiting the STING pathway. Furthermore, E5 promotes cell proliferation by activating the PI3K/AKT/mTOR pathway and facilitates angiogenesis by upregulating VEGF expression via HIF-1α. E5 also interferes with mitogenic signaling through activation of the MAPK pathway, promoting cell invasiveness by increasing MET expression.