人乳头瘤病毒（HPVs）感染口腔和肛交黏膜并可能引发癌症。高危（HR）HPV致癌蛋白E6和E7利用细胞因子促进细胞增殖，延迟分化并诱导基因组不稳定性，从而使感染细胞易于发生恶性转变。cAMP响应元件（CRE）结合蛋白1（CREB1）是一个可以充当原癌基因的主要转录因子，其异常活性与多种癌症相关。然而，关于HPV和CREB1在宫颈癌或HPV生命周期中的相互作用知之甚少。我们发现CREB在感染性HPV阳性的原代角质细胞中被激活，而CREB1的表达和磷酸化与HPV阳性宫颈疾病的进展相关。CREB1的耗竭或CREB1活性抑制导致细胞增殖减少，上皮向间质转变标记物表达减少，并伴随HPV阳性宫颈癌细胞系迁移减少。CREB1的表达受到肿瘤抑制microRNA miR-203a的负调控，而CREB1的磷酸化通过MAPK/MSK信号通路进行调控。重要的是，CREB1直接结合病毒启动子，上调E6/E7致癌基因的转录，从而建立了HPV致癌蛋白和CREB1之间的正反馈环。我们的发现证明了CREB1在HPV阳性宫颈癌中的致癌功能及其与HPV致癌基因的关系。 © 2023 The Authors. 《医学病毒学杂志》由Wiley Periodicals LLC出版。

Human papillomaviruses (HPVs) infect the oral and anogenital mucosa and can cause cancer. The high-risk (HR)-HPV oncoproteins, E6 and E7, hijack cellular factors to promote cell proliferation, delay differentiation and induce genomic instability, thus predisposing infected cells to malignant transformation. cAMP response element (CRE)-binding protein 1 (CREB1) is a master transcription factor that can function as a proto-oncogene, the abnormal activity of which is associated with multiple cancers. However, little is known about the interplay between HPV and CREB1 activity in cervical cancer or the productive HPV lifecycle. We show that CREB is activated in productively infected primary keratinocytes and that CREB1 expression and phosphorylation is associated with the progression of HPV+ cervical disease. The depletion of CREB1 or inhibition of CREB1 activity results in decreased cell proliferation and reduced expression of markers of epithelial to mesenchymal transition, coupled with reduced migration in HPV+ cervical cancer cell lines. CREB1 expression is negatively regulated by the tumor suppressor microRNA, miR-203a, and CREB1 phosphorylation is controlled through the MAPK/MSK pathway. Crucially, CREB1 directly binds the viral promoter to upregulate transcription of the E6/E7 oncogenes, establishing a positive feedback loop between the HPV oncoproteins and CREB1. Our findings demonstrate the oncogenic function of CREB1 in HPV+ cervical cancer and its relationship with the HPV oncogenes.© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.