Human Papillomavirus Oncoproteins Confer Sensitivity to Cisplatin by Interfering with Epidermal Growth Factor Receptor Nuclear Trafficking Related to More Favorable Clinical Survival Outcomes in Non-Small Cell Lung Cancer

Abstract

High-risk human papillomavirus (HPV) infections and epidermal growth factor receptor (EGFR) expression have been reported to be associated with more favorable survival outcomes in lung adenocarcinoma patients. In this study, we utilized transfected HPV 16E5/16E6/16E7 H292 cells to investigate the mechanism of HPV oncoproteins interfering with EGFR nuclear trafficking related to a better response to cisplatin. Furthermore, we correlated HPV 16E6/18E6 expression and differentially localized EGFR expression with the clinical association and survival impact in lung adenocarcinoma patients. Our results found significantly higher phosphorylated nuclear EGFR expression upon epidermal growth factor stimulus and better responses to cisplatin in transfected HPV 16E5/16E6/16E7 NCI-H292 cells and xenograft animal models. Our data were compatible with clinical results of a high correlation of HPV 16E6/18E6 and EGFR expression in non-small cell lung cancer tissues and the synergistic effects of both with the best survival prognosis in a lung adenocarcinoma cohort, especially in patients with older age, no brain metastasis, smoking history, and wild-type EGFR status. Cumulatively, our study supports HPV 16E5/16E6/16E7 oncoproteins interfering with EGFR nuclear trafficking, resulting in increased sensitivity to cisplatin. HPV 16E6/18E6 and EGFR expression serve as good prognostic factors in lung adenocarcinoma patients.

The Role of Human Papilloma Virus (HPV) in Primary Lung Cancer Development: State of the Art and Future Perspectives

“…According to their results, HPV16E6/18E6 and EGFR expression in NSCLC correlates with a greater survival rate in older lung adenocarcinoma patients without brain metastasis, with a smoking history, and with wild-type EGFR status. Additionally, this group of patients demonstrated an increased sensitivity to cisplatin-based chemotherapy due to the action of HPV16E5/16E6/16E7 oncoproteins on EGFR nuclear trafficking [57]. Other data available in the literature further support these observations, showing better prognosis, higher survival rates [58], and longer metastatic-free survival [26] in HPV18-and 19-positive NSCLCs compared to negative forms.…”

“…The underlying reasons behind the favorable prognosis associated with HPV infection in NSCLC remain unknown. A possible explanation could be derived from a recent study (October 2022), where Wang et al [57] showed how HPV immortalizes cancer cells not only by inhibiting tumor suppressors (Rb and p53) but also by activating the EGFR pathway. According to their results, HPV16E6/18E6 and EGFR expression in NSCLC correlates with a greater survival rate in older lung adenocarcinoma patients without brain metastasis, with a smoking history, and with wild-type EGFR status.…”

“…Prior to the first report by Wang et al [57] in 2022, the role of HPV lung infection in the aggressiveness of lung cancer was completely unexplored. However, the growing evidence supporting a better prognosis for HPV-positive NSCLC has pushed to consider HPV status as an important biomarker in the therapeutic pathway of these patients.…”

“…However, the growing evidence supporting a better prognosis for HPV-positive NSCLC has pushed to consider HPV status as an important biomarker in the therapeutic pathway of these patients. Due to a lack of evidence until recent relevant studies were published, testing for HPV status of lung cancer cells was only performed in research settings and was not a part of routine clinical practice [32,56,57].…”

Advancing Immunotherapies for HPV-Related Cancers: Exploring Novel Vaccine Strategies and the Influence of Tumor Microenvironment

“…The detection of HPV DNA has been repeatedly reported in lung tumors worldwide [ 33 , 34 , 35 , 36 ], and while the association between infection and tumor progression is unclear, a recent study developed by Wang and collaborators investigated the possible interference of oncoproteins E5, E6, and E7 of HPV-16 transfected in H292 cells in the expression of the nuclear epidermal growth factor receptor (EGFR), where higher levels of EGFR were associated with greater sensitivity to cisplatin, a chemotherapeutic widely used to treat cancers [ 37 ].…”