Human papillomavirus (HPV) is associated with the development of head and neck squamous cell carcinomas (HNSC). Cisplatin is used to treat HNSC and induces DNA adducts including interstrand crosslinks (ICLs). Previous reports have shown that HPV positive HNSC patients respond better to cisplatin therapy. Our previous reports highlight that loss of base excision repair (BER) and mismatch repair (MMR) results in cisplatin resistance. Of importance, uracil DNA glycosylase (UNG) is required to initiate the BER response to cisplatin treatment and maintain drug sensitivity. These previous results highlight that specific cytidine deaminases could play an important role in the cisplatin response by activating the BER pathway to mediate drug sensitivity. The APOBEC3 (A3) family of cytidine deaminases are enzymes that restrict HPV as part of the immune defense to viral infection. In this study, the Cancer Genome Atlas (TCGA) HNSC data were used to assess the association between the expression of the seven proteins in the A3 cytidine deaminase family, HPV-status and survival outcomes. Higher A3 G expression in HPV-positive tumors corresponds with better overall survival (OS) (HR 0.33, 95 % CI 0.11-0.93, p = 0.04). FaDu and Scc-25 HNSC cell lines were used to assess alterations in A3, BER and MMR expression in response to cisplatin. We demonstrate that A3, Polβ, and MSH6 knockdown in HNSC cells results in resistance to cisplatin and carboplatin as well as an increase in the rate of ICL removal in FaDu and Scc-25 HNSC cells. Our results suggest that A3s activate BER in HNSC, mediate repair of cisplatin ICLs and thereby, sensitize cells to cisplatin which likely contributes to the improved patient responses observed in HPV infected patients.

中文翻译：

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HPV 诱导的 APOBEC3 酶介导头颈癌的总体生存率和对顺铂的反应。

人乳头瘤病毒 (HPV) 与头颈鳞状细胞癌 (HNSC) 的发生有关。顺铂用于治疗 HNSC 并诱导 DNA 加合物，包括链间交联 (ICL)。之前的报告显示，HPV 阳性的 HNSC 患者对顺铂治疗反应更好。我们之前的报告强调，碱基切除修复 (BER) 和错配修复 (MMR) 的缺失会导致顺铂耐药。重要的是，需要尿嘧啶 DNA 糖基化酶 (UNG) 来启动对顺铂治疗的 BER 反应并维持药物敏感性。这些先前的结果强调，特定的胞苷脱氨酶可以通过激活 BER 途径介导药物敏感性，在顺铂反应中发挥重要作用。APOBEC3 (A3) 胞苷脱氨酶家族是限制 HPV 的酶，作为病毒感染免疫防御的一部分。在这项研究中，癌症基因组图谱 (TCGA) HNSC 数据用于评估 A3 胞苷脱氨酶家族中七种蛋白的表达、HPV 状态和生存结果之间的关联。HPV 阳性肿瘤中较高的 A3 G 表达与较好的总生存期 (OS) 相对应（HR 0.33，95 % CI 0.11-0.93，p = 0.04）。FaDu 和 Scc-25 HNSC 细胞系用于评估顺铂响应下 A3、BER 和 MMR 表达的变化。我们证明 HNSC 细胞中的 A3、Polβ 和 MSH6 敲低会导致对顺铂和卡铂的耐药性，并增加 FaDu 和 Scc-25 HNSC 细胞中 ICL 去除率。我们的结果表明，A3 激活 HNSC 中的 BER，介导顺铂 ICL 的修复，从而使细胞对顺铂敏感，这可能有助于改善在 HPV 感染患者中观察到的患者反应。