ABSTRACT

Oropharyngeal squamous cell carcinoma (OPSCC) is an increasing world health problem with a more favorable prognosis for patients with human papillomavirus (HPV)-positive tumors compared to those with HPV-negative OPSCC. How HPV confers a less aggressive phenotype, however, remains undefined. We demonstrated that HPV-positive OPSCC cells display reduced macroautophagy/autophagy activity, mediated by the ability of HPV-E7 to interact with AMBRA1, to compete with its binding to BECN1 and to trigger its calpain-dependent degradation. Moreover, we have shown that AMBRA1 downregulation and pharmacological inhibition of autophagy sensitized HPV-negative OPSCC cells to the cytotoxic effects of cisplatin. Importantly, semi-quantitative immunohistochemical analysis in primary OPSCCs confirmed that AMBRA1 expression is reduced in HPV-positive compared to HPV-negative tumors. Collectively, these data identify AMBRA1 as a key target of HPV to impair autophagy and propose the targeting of autophagy as a viable therapeutic strategy to improve treatment response of HPV-negative OPSCC.

Abbreviations: AMBRA1: autophagy and beclin 1 regulator 1; CDDP: cisplatin (CDDP); FFPE: formalin-fixed paraffin-embedded (FFPE); HNC: head and neck cancers (HNC); HPV: human papillomavirus (HPV); hrHPV: high risk human papillomavirus (hrHPV); OCSCC: oral cavity squamous carcinomas (OCSSC); OPSCC: oropharyngeal squamous cell carcinoma (OPSCC); OS: overall survival (OS); qPCR: quantitative polymerase chain reaction; RB1: RB transcriptional corepressor 1; ROC: receiver operating characteristic curve (ROC).

 抽象的

口咽鳞状细胞癌 (OPSCC) 是一个日益严重的世界健康问题，与 HPV 阴性 OPSCC 患者相比，人乳头瘤病毒 (HPV) 阳性肿瘤患者的预后更好。然而，HPV 如何赋予攻击性较小的表型仍不清楚。我们证明，HPV 阳性 OPSCC 细胞表现出巨自噬/自噬活性降低，这是由 HPV-E7 与 AMBRA1 相互作用、竞争其与 BECN1 的结合并触发其钙蛋白酶依赖性降解的能力介导的。此外，我们还发现，AMBRA1 下调和自噬的药理学抑制使 HPV 阴性 OPSCC 细胞对顺铂的细胞毒性作用敏感。重要的是，原发性 OPSCC 的半定量免疫组织化学分析证实，与 HPV 阴性肿瘤相比，HPV 阳性肿瘤中的 AMBRA1 表达降低。总的来说，这些数据将 AMBRA1 确定为 HPV 损害自噬的关键靶标，并提出以自噬为目标作为改善 HPV 阴性 OPSCC 治疗反应的可行治疗策略。

缩写：AMBRA1：自噬和 beclin 1 调节器 1； CDDP：顺铂（CDDP）； FFPE：福尔马林固定石蜡包埋（FFPE）； HNC：头颈癌（HNC）； HPV：人乳头瘤病毒（HPV）； hrHPV：高危人乳头瘤病毒（hrHPV）； OCSCC：口腔鳞状细胞癌（OCSSC）； OPSCC：口咽鳞状细胞癌（OPSCC）； OS：总生存期（OS）； qPCR：定量聚合酶链式反应； RB1：RB转录辅阻遏物1； ROC：受试者工作特征曲线（ROC）。