Department of Otorhinolaryngology - Head and Neck Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
J Virol. 2022 Nov 23;96(22):e0132622. doi: 10.1128/jvi.01326-22. Epub 2022 Nov 7.
The human papillomavirus (HPV) E6 and E7 oncogenes are expressed at all stages of HPV-mediated carcinogenesis and are essential drivers of cancers caused by high-risk HPV. Some of the activities of HPV E6 and E7, such as their interactions with host cellular tumor suppressors, have been characterized extensively. There is less information about how high-risk HPV E6 and E7 alter cellular responses to cytokines that are present in HPV-infected tissues and are an important component of the tumor microenvironment. We used several models of HPV oncoprotein activity to assess how HPV16 E6 and E7 alter the cellular response to the proinflammatory cytokine IL-1β. Models of early stage HPV infection and of established HPV-positive head and neck cancers exhibited similar dysregulation of IL-1 pathway genes and suppressed transcriptional responses to IL-1β treatment. Such overlap in cell responses supports that changes induced by HPV16 E6 and E7 early in infection could persist and contribute to a dysregulated immune environment throughout carcinogenesis. HPV16 E6 and E7 also drove the upregulation of several suppressors of IL-1 cytokine signaling, including SIGIRR, both in primary keratinocytes and in cancer cells. SIGIRR knockout was insufficient to increase IL-1β-dependent gene expression in the presence of HPV16 E6 and E7, suggesting that multiple suppressors of IL-1 signaling contribute to dampened IL-1 responses in HPV16-positive cells. Human papillomavirus (HPV) infection is responsible for nearly 5% of the worldwide cancer burden. HPV-positive tumors develop over years to decades in tissues that are subject to frequent stimulation by proinflammatory cytokines. However, the effects of HPV oncoproteins on the cellular response to cytokine stimulation are not well defined. We analyzed IL-1 cytokine signaling in several models of HPV biology and disease. We found that HPV16 E6 and E7 oncoproteins mediate a broad and potent suppression of cellular responses to IL-1β in models of both early and late stages of carcinogenesis. Our data provide a resource for future investigation of IL-1 signaling in HPV-positive cells and cancers.
人乳头瘤病毒（HPV）E6 和 E7 癌基因在 HPV 介导的癌变的所有阶段表达，是高危 HPV 引起的癌症的主要驱动因素。HPV E6 和 E7 的一些活性，例如它们与宿主细胞肿瘤抑制因子的相互作用，已经得到了广泛的描述。关于高危 HPV E6 和 E7 如何改变细胞对 HPV 感染组织中存在的细胞因子的反应，以及这些细胞因子是肿瘤微环境的重要组成部分，信息较少。我们使用几种 HPV 癌蛋白活性模型来评估 HPV16 E6 和 E7 如何改变细胞对促炎细胞因子 IL-1β 的反应。早期 HPV 感染模型和已建立的 HPV 阳性头颈部癌症模型表现出类似的 IL-1 途径基因失调和对 IL-1β 治疗的转录反应抑制。细胞反应的这种重叠表明，HPV16 E6 和 E7 在感染早期诱导的变化可能持续存在，并导致整个癌变过程中免疫环境失调。HPV16 E6 和 E7 还在原代角质形成细胞和癌细胞中上调了几种 IL-1 细胞因子信号的抑制剂，包括 SIGIRR。SIGIRR 敲除不足以增加 HPV16 E6 和 E7 存在时 IL-1β 依赖性基因表达，这表明 IL-1 信号的多个抑制剂有助于抑制 HPV16 阳性细胞中的 IL-1 反应。人乳头瘤病毒（HPV）感染占全球癌症负担的近 5%。HPV 阳性肿瘤在经常受到促炎细胞因子刺激的组织中经过数年至数十年的发展。然而，HPV 癌蛋白对细胞对细胞因子刺激反应的影响尚未明确。我们分析了几种 HPV 生物学和疾病模型中的 IL-1 细胞因子信号。我们发现 HPV16 E6 和 E7 癌蛋白在致癌作用的早期和晚期模型中广泛而有力地抑制了细胞对 IL-1β 的反应。我们的数据为未来研究 HPV 阳性细胞和癌症中的 IL-1 信号提供了资源。
