The Different Response Of HPV-Positive And-Negative HNSCC Cells To As₂O₃ And Its Mechanism

Head and neck squamous cell carcinoma（HNSCC）is one of the most common type of the head and neck malignant tumors.It can be divided into two types:human papillomavirus（HPV）positive and negative.HPV positive HNSCCs account for about 20%,and oncogenic viral proteins E6 and E7 are the main drivers of this type.Current studies have shown that arsenic trioxide（As₂O₃）has a significant therapeutic effect on hematological diseases,and it also has an anticancer effect on variety of solid tumors.However,the pharmacological action and anticancer mechanism of As₂O₃ on HNSCC remains unknown.In this study,we systematically investigated the anticancer effect and potential mechanism of As₂O₃ on the HPV-16 positive and HPV negative HNSCC cells.The cell proliferation assay showed that HPV-16 positive HNSCC cells were more sensitive to growth inhibition induced by As₂O₃ than HPV negative HNSCC cells.The different sensitivity to As₂O₃ in HPV-16 positive and HPV negative HNSCC cells may be associated with the genetic background and the pathogenesis.The results of key genes/proteins basal expression in HNSCC cells indicate that HPV negative HNSCC cells have more obvious genomic changes than HPV-16 positive HNSCC cells.In HPV negative HNSCC cells,the TP53 is a mutant type.The lower expression or lack of p16 and High expression of EGFR play an important role in the development of HPV negative HNSCC.HPV positive HNSCC cells harbour less genetic changes,and the HPV oncogenes play important roles in tumorigenesis.In addition to inhibiting the proliferation of HNSCC cells with As₂O₃,it also play an anti-tumor role by inhibits the colony formation and migration of HNSCC cells,induces HNSCC cells apoptosis and changes the HNSCC cells cycle distribution.Animal experiments have shown that As₂O₃ can inhibits the growth of HNSCC xenograft tumors.The anti-tumor mechanism of As₂O₃on HNSCC cells may be associated with the alteration of key genes/proteins.In HPV negative HNSCC cells,the protein expression levels of EGFR,cyclin D1 and p53（mutant type）were reduced and the protein expression levels of Rb was up-regulated following treatment with As₂O₃.In HPV-16 positive HNSCC cells,the protein expression levels of E6/E7 and cyclin D1 were reduced and the protein expression levels of p16,p53（wild type）and Rb were up-regulated following treatment with As₂O₃.The results show that As₂O₃ is a potential drug for the treatment of HNSCC.