Abstract

Head and neck squamous cell carcinoma (HNSCC) has a variety of causes. Recently, the human papilloma virus (HPV) has been implicated in the rising incidence of oropharyngeal cancer and has led to variety of studies exploring the differences between HPV-positive and HPV-negative HNSCC. The calcium-activated chloride channel TMEM16A is overexpressed in a variety of cancers, including HNSCC, but whether or not it plays different roles in HPV-positive and HPV-negative HNSCC is unknown. Here, we demonstrate that TMEM16A is preferentially overexpressed in HPV-negative HNSCC and that this overexpression of TMEM16A is associated with decreased patient survival. We also show that TMEM16A expression is decreased in HPV-positive HNSCC at the DNA, RNA, and protein levels in patient samples as well as cell lines. We demonstrate that the lower levels of TMEM16A expression in HPV-positive tumors can be attributed to both a combination of copy number alteration and promoter methylation at the DNA level. Additionally, our cellular data show that HPV-negative cell lines are more dependent on TMEM16A for survival than HPV-positive cell lines. Therefore, we suspect that the down-regulation of TMEM16A in HPV-positive HNSCC makes TMEM16A a poor therapeutic target in HPV-positive HNSCC, but a potentially useful target in HPV-negative HNSCC.

Highlights

  • Head and neck squamous cell carcinoma (HNSCC) has a variety of causes

  • TMEM16A/ANO1 has been found to be overexpressed in numerous cancers, including esophageal, gastrointestinal stromal tumors, and head and neck cancers[7,8,9]

  • Previous studies on this protein in HNSCC have shown that overexpression leads to activation of the RAS-RAF-MEK-ERK1/2 pathway, increased cellular proliferation, and decreased patient survival[9]

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Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) has a variety of causes. Recently, the human papilloma virus (HPV) has been implicated in the rising incidence of oropharyngeal cancer and has led to variety of studies exploring the differences between HPV-positive and HPV-negative HNSCC. The calcium-activated chloride channel TMEM16A is overexpressed in a variety of cancers, including HNSCC, but whether or not it plays different roles in HPV-positive and HPV-negative HNSCC is unknown. We demonstrate that TMEM16A is preferentially overexpressed in HPV-negative HNSCC and that this overexpression of TMEM16A is associated with decreased patient survival. We show that TMEM16A expression is decreased in HPV-positive HNSCC at the DNA, RNA, and protein levels in patient samples as well as cell lines. Head and neck squamous cell carcinoma (HNSCC) represents the sixth most common cancer in the world and has an overall five-year survival of approximately 50%1. TMEM16A ( called TAOS2, ANO1, and DOG1), a calcium-activated chloride channel[6], has been shown to be overexpressed in numerous cancers, including esophageal[7], gastrointestinal stromal tumors[8], and HNSCC9. Overexpression of TMEM16A correlates with decreased patient survival in HNSCC9

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