HPV 양성 두경부암에서 방사선 저항성 예측 바이오마커 개발: TP53 mutation 및 SOX2 역할 규명

Abstract

Abstract Background: HPV-positive OPSCC patients tend to be non/low-smokers and drinkers, as well as younger and overall healthier than their HPV-negative counterparts. Given the high survivorship in HPV-positive OPSCC, there is great interest in de-intensifying therapy. However, approximately 15% of HPV-positive OPSCC patients fail standard therapy. Robust biomarkers of radiation resistance would be highly useful to exclude high-risk patients from deintensification protocols and instead direct them towards intensified treatment. The aim of this study is to validate the molecular subgroups presenting radiation resistance and investigate the mechanism of tumor aggressiveness and radiation resistance in HPV-positive OPSCC

Methods: We introduced the TP53 mutation into two novel, treatment naive HPV-positive cell line. MTT assay, migration and invasion assay and clonogenic assay was performed to compare the tumor growth, aggressiveness and radiation resistance in both parental and TP53 mutation cell line in vitro. Microarray and western blot were performed to detect robust biomarkers in TP53 mutation HPV-positive cell line compared with parental cell line. We confirmed the in vitro data through in vivo study.

Results: TP53 mutation cell line with increased ability of migration and invasiveness showed resistance to radiation compared to TP53 wild HPV-positive cell line. We found that SOX2 was expressed predominantly in the TP53 mutation cell line on microarray and confirmed the findings through western blot. And we demonstrated that SOX2 mediated the tumor migration and invasiveness and radiation resistance in TP53 mutation cell lines. Inhibition of SOX2 enhanced radiation sensitivity in the TP53 mutation cell line in vitro and in vivo study.

Conclusions: SOX2 is overexpressed in TP53 mutation HPV-positive OPSCC and plays a crucial role in the development of radiation resistance by regulating tumor invasiveness.