HPV sensitizes OPSCC cells to cisplatin-induced apoptosis by inhibiting autophagy through E7-mediated degradation of AMBRA1.
HPV sensitizes OPSCC cells to cisplatin-induced apoptosis by inhibiting autophagy through E7-mediated degradation of AMBRA1.
复制标题
DOI：
10.1080/15548627.2020.1847444
复制
发表时间：
2021-10
期刊：
影响因子：
13.3
通讯作者：
Fimia GM
中科院分区：
文献类型：
--
作者：
Antonioli M;Pagni B;Vescovo T;Ellis R;Cosway B;Rollo F;Bordoni V;Agrati C;Labus M;Covello R;Benevolo M;Ippolito G;Robinson M;Piacentini M;Lovat P;Fimia GM
口咽鳞状细胞癌（OPSCC）是一个日益严重的世界性健康问题，与HPV阴性OPSCC患者相比，HPV阳性肿瘤患者的预后更好。然而，HPV如何赋予较低的侵袭性表型仍不明确。我们证明，HPV阳性OPSCC细胞显示减少的巨自噬/自噬活性，介导的HPV-E7与AMBRA 1相互作用的能力，竞争与BECN 1的结合，并触发其钙蛋白酶依赖性降解。此外，我们已经表明，AMBRA 1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，在原发性OPSCC中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AMBRA 1表达降低。总的来说，这些数据将AMBRA 1确定为HPV损害自噬的关键靶标，并提出自噬靶向作为改善HPV阴性OPSCC治疗反应的可行治疗策略。缩略语：AMBRA 1：自噬和beclin 1调节因子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：定量聚合酶链反应; RB1：RB转录辅阻遏物1; ROC：受试者工作特征曲线（ROC）。
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).
登录
查看更多内容
DOI：
10.1038/s41579-018-0003-6
发表时间：
2018-06
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
Choi Y;Bowman JW;Jung JU
通讯作者：
Jung JU
影响因子：
3.8
作者：
Lai K;Matthews S;Wilmott JS;Killingsworth MC;Yong JL;Caixeiro NJ;Wykes J;Samakeh A;Forstner D;Lee M;McGuinness J;Niles N;Hong A;Ebrahimi A;Lee CS
通讯作者：
Lee CS
影响因子：
168.9
作者：
Mehanna, Hisham;Robinson, Max;Dunn, Janet
通讯作者：
Dunn, Janet
影响因子：
64.8
作者：
Fimia, Gian Maria;Stoykova, Anastassia;Cecconi, Francesco
通讯作者：
Cecconi, Francesco
影响因子：
10.3
作者：
Ellis, R.;Tang, D.;Lovat, P. E.
通讯作者：
Lovat, P. E.