TMEM16A/ANO1 is differentially expressed in HPV-negative versus HPV-positive head and neck squamous cell carcinoma through promoter methylation.
TMEM16A/ANO1 is differentially expressed in HPV-negative versus HPV-positive head and neck squamous cell carcinoma through promoter methylation.
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DOI：
10.1038/srep16657
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发表时间：
2015-11-13
影响因子：
4.6
通讯作者：
Duvvuri U
中科院分区：
文献类型：
--
作者：
Dixit R;Kemp C;Kulich S;Seethala R;Chiosea S;Ling S;Ha PK;Duvvuri U
头颈鳞状细胞癌（HNSCC）有多种病因。最近，人乳头瘤病毒 (HPV) 与口咽癌发病率上升有关，并引发了各种研究来探索 HPV 阳性和 HPV 阴性 HNSCC 之间的差异。钙激活氯离子通道 TMEM16A 在包括 HNSCC 在内的多种癌症中过度表达，但其在 HPV 阳性和 HPV 阴性 HNSCC 中是否发挥不同作用尚不清楚。在这里，我们证明 TMEM16A 在 HPV 阴性 HNSCC 中优先过表达，并且 TMEM16A 的过表达与患者生存率降低相关。我们还表明，在 HPV 阳性 HNSCC 患者样本和细胞系的 DNA、RNA 和蛋白质水平上，TMEM16A 表达降低。我们证明，HPV 阳性肿瘤中 TMEM16A 表达水平较低可归因于 DNA 水平上的拷贝数改变和启动子甲基化的组合。此外，我们的细胞数据表明，HPV 阴性细胞系比 HPV 阳性细胞系更依赖 TMEM16A 生存。因此，我们怀疑 HPV 阳性 HNSCC 中 TMEM16A 的下调使得 TMEM16A 成为 HPV 阳性 HNSCC 的不良治疗靶点，但成为 HPV 阴性 HNSCC 的潜在有用靶点。
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.