Loss of HPV type 16 E7 restores cGAS-STING responses in human papilloma virus-positive oropharyngeal squamous cell carcinomas cells
Loss of HPV type 16 E7 restores cGAS-STING responses in human papilloma virus-positive oropharyngeal squamous cell carcinomas cells
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DOI：
10.1016/j.jmii.2020.07.010
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发表时间：
2021-08-20
影响因子：
7.4
通讯作者：
Idris, Adi
中科院分区：
文献类型：
--
作者：
Bortnik, Vuk;Wu, Michelle;Idris, Adi
人乳头瘤病毒（HPV）是子宫颈癌和口咽癌的罪魁祸首。HPV阳性（+）癌症被认为是“癌基因成瘾”，表现出对癌基因持续表达的绝对需求，因为它们的生存能力，因此使这些基因成为开发特定治疗剂的突出目标。HPV和口咽鳞状细胞癌（OPSCC）之间有很强的相关性，OPSCC是头颈癌（HNCs）的一个子集。令人震惊的是，HPV相关的OPSCC在全球范围内呈上升趋势，HPV + OPSCC的病例数超过了美国宫颈癌的病例数。在这里，我们发现主要的HPV癌基因E6和E7对HPV阳性（+）OPSCCs的生存至关重要，使这些癌基因成为HPV驱动的OPSCCs的重要靶点。已知HPV E7与STING相互作用，STING是病毒dna传感cGAS-STING机制的一个组成部分，可激活典型的抗病毒I型干扰素（IFN）反应。我们最近的研究表明，来自HPV 16型的E7负责阻断HPV + OPSCC细胞中的cGAS-STING反应。在这项研究中，我们发现CRISPR/ cas9介导的HPV + OPSCC细胞SCC2和SCC104中E7的缺失恢复了cGAS-STING反应。未来的工作可能涉及HPV癌基因靶向导致HPV + OPSCC肿瘤消退，并且联合使用STING激动剂可以通过激活适当的抗肿瘤反应诱导有利的肿瘤清除。台湾省微生物学会版权所有由爱思唯尔台湾有限责任公司发布。这是一篇基于CC by-nc-nd许可（http://creativecommons.org/licenses/by-nc-nd/4.0/）的开放获取文章。
Human papilloma viruses (HPV) are the main culprit in cervical and oropharyngeal cancers. HPV positive (+) cancers are regarded as 'oncogene addicted', displaying an absolute requirement for the continued expression of the oncogenes for their viability owing their survival, and thus making these genes salient targets for developing specific therapeutic agents. There is a strong association between HPV and oropharyngeal squamous cell carcinomas (OPSCC), a subset of head and neck cancers (HNCs). Alarmingly, HPV-associated OPSCC are on the rise globally, and the number of cases of HPV + OPSCCs surpasses that of cervical cancer in the USA. Here, we show that major HPV oncogenes, E6 and E7, are essential for the survival of HPV positive (+) OPSCCs, making these oncogenes salient targets for HPV-driven OPSCCs. HPV E7 is known to interact with STING, a component of the viral DNA-sensing cGAS-STING machinery which activates a pro-typical anti-viral type I interferon (IFN) response. Our recent work showed that E7 from HPV type 16 is responsible for the blockade of cGAS-STING responses in HPV + OPSCC cells. In this study, we show that CRISPR/Cas9-mediated loss of E7 from HPV + OPSCC cells, SCC2 and SCC104, restored cGAS-STING responses. Future work could involve HPV oncogene targeting leading to HPV + OPSCC tumour regression and that the combined use of STING agonists would induce favourable tumour clearance by activating appropriate anti-tumour responses. Copyright 2020, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).