cGAS-STING responses are dampened in high-risk HPV type 16 positive head and neck squamous cell carcinoma cells

Abstract

Head and neck cancers (HNCs) are a major health problem and a leading cause of morbidity and mortality worldwide. More than 90% of these tumours are head and neck squamous cell carcinomas (HNSCCs). Amongst the common risk factors for HNCs (tobacco and alcohol use), there is a strong association of human papillomavirus (HPV) with HNSCCs. HPV type 16 (HPV 16), the major high-risk HPV type, is most commonly associated with HPV-driven HNSCCs. The promiscuous nature of the major HPV oncogene, E7, allows its interaction with a myriad of host proteins including STING, a component of the viral DNA-sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) machinery. Sensing of viral DNA by the cGAS-STING machinery results in a type I interferon (IFN)mediated anti-viral response. Amelioration of IFN responses resulting from the direct blockade of STING by E7 was first demonstrated in high-risk HPV type 18 (HPV 18) positive (+) cervical squamous cell carcinoma (CESC) cells. However, the role of E7 from HPV 16 (HPV 16E7) in antagonising cGAS-STING responses have not been investigated, let alone in the context of HNSCCs. Here, we show that HPV 16E7+, but not HPV 16E7 negative (-), HNSCC cells respond poorly to cGAS-STING activation stimulus. We further confirm that this inhibition occurred via the highly conserved LXCXE motif in 16E7. This finding contributes to the better understanding of role of high-risk HPV E7 in blocking cGAS-STING pathway, especially in the context of HNSCCs.

Papilomavírus Humano enquanto fator etiológico do Carcinoma Epidermoide Bucal

“…No estudo epidemiológico-clínico de Mushfiq et al 32 foi enfatizado que os tumores associados ao HPV-16 e HPV-18 localizados na língua e na área gengival podem ocasionar consequências mais graves para os pacientes, como, por exemplo, incapacidade de deglutir, mastigar e dificuldades durante a emissão da fala, sendo que elevados índices de mortalidade são associados aos cânceres epidermoides bucais que se desenvolvem na região lingual 28 .…”

“…Entretanto, barreiras sociais ainda precisam ser ultrapassadas para que esses profissionais consigam intervir de maneira eficaz em fatores determinantes para o processo de saúde-doença de seus pacientes [33][34][35] . Tais barreiras incluem, principalmente, a dificuldade da abordagem de assuntos relacionados a doenças sexualmente transmissíveis, como o HPV [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] .…”

“…Ressalta-se, ainda, que o exame clínico e o adequado acompanhamento permitem que ocorra a detecção de diversas lesões, anomalias e alterações na cavidade bucal [22][23][24][25][26][27][28][29][30][31][32][33][34][35] . Ademais, a identificação precoce de lesões potencialmente malignas, como o carcinoma epidermoide bucal, permite que as chances de cura aumentem consideravelmente 33 .…”

<p>The Relationship Between Human Papillomavirus, OFD1 and Primary Ciliogenesis in the Progression of Oropharyngeal Cancer: A Retrospective Cohort Study</p>

“…2 90% of HPV-positive OP cancers are infected with high-risk HPV16 (the dominant subtype). 6 In cancers associated with HPV infection, the viral oncoproteins E6 and E7 are always overexpressed. E7 can bind to the retinoblastoma (Rb) protein and destroy the E2F/Rb complex.…”

“…Previous studies have indicated that regardless of the HPV infection status in the oropharynx, p16 protein can independently serve as a predictor of radiotherapy response. 6,7 Among patients undergoing surgery and postoperative adjuvant radiotherapy, the overall survival and disease-specific survival of patients with positive p16 protein were significantly longer than those with negative p16. 8 The results shown in our univariate analysis are consistent with it.…”