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

SIMPLE SUMMARY: Lung cancer is the leading cause of cancer death in the world. Identifying prognostic factors is crucial to improve the survival time of those with lung cancer. Our previous studies have reported that human papillomavirus (HPV) infections and epidermal growth factor receptor (EGFR) expression are associated with a better survival prognosis in lung adenocarcinoma. The purpose of this study was to detect the molecular evidence of HPV oncoproteins interfering with EGFR nuclear trafficking related to better prognosis in lung cancer. Based on the study results for a better response to cisplatin in transfected HPV 16E5/16E6/16E7 H292 xenograft animal models, as well as better survival in lung adenocarcinoma patients with either 16E6/18E6 or EGFR expression, we suggest that clinicians should adjust the treatment protocol according to HPV 16E6/18E6 expression and EGFR expression to increase the overall survival time in 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.