Misregulation of DNA damage repair pathways in HPV-positive head and neck squamous cell carcinoma contributes to cellular radiosensitivity.
Misregulation of DNA damage repair pathways in HPV-positive head and neck squamous cell carcinoma contributes to cellular radiosensitivity.
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DOI：
10.18632/oncotarget.16265
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发表时间：
2017-05-02
期刊：
影响因子：
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通讯作者：
Parsons JL
中科院分区：
文献类型：
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作者：
Nickson CM;Moori P;Carter RJ;Rubbi CP;Parsons JL
与 HPV 阴性形式的疾病相比，16 型人乳头瘤病毒 (HPV) 相关口咽鳞状细胞癌 (OPSCC) 患者对放疗的敏感性更高，生存率也更高。然而，造成这种特征差异的细胞机制尚不清楚。在这里，我们研究了 DNA 损伤修复途径对 OPSCC 细胞系体外放射敏感性的贡献。我们证明，两个 HPV 阳性 OPSCC 细胞确实比两个 HPV 阴性 OPSCC 细胞对放射更敏感，这与电离辐射 (IR) 诱导的 DNA 双链断裂 (DSB) 修复效率降低相关。有趣的是，我们发现 HPV 阳性 OPSCC 细胞的 XRCC1、DNA 聚合酶 β、PNKP 和 PARP-1 蛋白水平上调，这些蛋白参与碱基切除修复 (BER) 和单链断裂 (SSB) 修复。这意味着这些细胞修复 DNA 碱基损伤和 SSB 的能力和效率有所提高。此外，我们还证明，HPV 阳性（但更有趣的是 HPV 阴性）OPSCC 与 PARP 抑制剂奥拉帕尼联合使用时显示出放射敏感性增加。这表明PARP抑制与放射治疗相结合可能是治疗两种形式OPSCC的有效方法，特别是对于相对具有放射抗性的HPV阴性OPSCC。
Patients with human papillomavirus type 16 (HPV)-associated oropharyngeal squamous cell carcinomas (OPSCC) display increased sensitivity to radiotherapy and improved survival rates in comparison to HPV-negative forms of the disease. However the cellular mechanisms responsible for this characteristic difference are unclear. Here, we have investigated the contribution of DNA damage repair pathways to the in vitro radiosensitivity of OPSCC cell lines. We demonstrate that two HPV-positive OPSCC cells are indeed more radiosensitive than two HPV-negative OPSCC cells, which correlates with reduced efficiency for the repair of ionising radiation (IR)-induced DNA double strand breaks (DSB). Interestingly, we show that HPV-positive OPSCC cells consequently have upregulated levels of the proteins XRCC1, DNA polymerase β, PNKP and PARP-1 which are involved in base excision repair (BER) and single strand break (SSB) repair. This translates to an increased capacity and efficiency for the repair of DNA base damage and SSBs in these cells. In addition, we demonstrate that HPV-positive but interestingly more so HPV-negative OPSCC display increased radiosensitivity in combination with the PARP inhibitor olaparib. This suggests that PARP inhibition in combination with radiotherapy may be an effective treatment for both forms of OPSCC, particularly for HPV-negative OPSCC which is relatively radioresistant.