Mechanism of HPV E6 oncogene mediated silencing of Syntenin-2 gene expression and role of Syntenin-2 in skin homeostasis.

HPV E6 癌基因介导 Syntenin-2 基因表达沉默的机制以及 Syntenin-2 在皮肤稳态中的作用。

• 批准号: 238937251
• 负责人: Professor Dr. Baki Akgül, Ph.D.
• 金额: --
• 依托单位: Institut für Virologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/238937251?language=en
• 关键词: Mechanism; HPV; E6; oncogene; mediated

Human papillomaviruses (HPV) are associated with the development of epithelial cancers and high-risk HPV of the genus alphapapillomavirus (alphaPV) have been proven to be a necessary causative factor for cervical cancer. HPV types of genus betapapillomavirus (betaPV) have been implicated in the development of cutaneous tumours, especially squamous cell carcinomas (SCC) and actinic keratosis. The E6 proteins from high-risk alphaPV (e.g. HPV16) are characterized by the presence of a PDZ binding motif, through which they interact with a number of cellular PDZ domain-containing substrates and cooperate in their degradation. PDZ proteins play a major role in maintenance of cell polarity, formation of cell-cell adherence junctions, and organization of multiprotein signaling complexes as scaffolding proteins. Their targeting by E6 may cause loss of cell polarity and morphological conversion, associated with epithelial-mesenchymal transition, leading to transformation and carcinogenesis. The ability of these E6 proteins to bind to PDZ domain proteins correlates with the oncogenic potential of the virus. The E6 proteins of oncogenic HPV from betaPV (e.g. HPV8) do not encode a PDZ-binding motif. We recently found, that the PDZ domain protein Syntenin-2 is transcriptionally downregulated in primary human epidermal keratinocytes (PHEK) by HPV8-E6. The mRNA levels of the known HPV16-E6 PDZ protein-targets Dlg, Scribble, Magi-1/-3, PSD95 and Mupp1 were not changed by HPV8-E6. Surprisingly, HPV16-E6 also repressed transcription of Syntenin-2 but with a lesser efficiency than HPV8-E6. These results identified Syntenin-2 as the first PDZ-domain protein being controlled by HPV8 and HPV16 at mRNA level. ShRNA mediated knock-down of Syntenin-2 led to an inhibition of differentiation and an increase in proliferation capacity in PHEK. We therefore hypothesize that a comprehensive evaluation of Syntenin-2 gene expression will define the specific contribution of Syntenin-2 in skin homeostasis and keratinocyte proliferation and immortalization. In addition, understanding of the regulatory mechanisms through which the high-risk HPV types 8 and 16 control Syntenin-2 gene expression may be of critical importance and may provide further aspects for our understanding of HPV pathogenesis in the future.

人乳头瘤病毒（HPV）与上皮癌的发生有关，并且已证明人乳头瘤病毒属的高危型HPV（alphaPV）是宫颈癌的必要致病因素。β乳头瘤病毒属的HPV类型（betaPV）与皮肤肿瘤的发生有关，特别是鳞状细胞癌（SCC）和光化性角化病。来自高危alphaPV（例如HPV 16）的E6蛋白的特征在于存在PDZ结合基序，通过该基序，它们与许多含有PDZ结构域的细胞底物相互作用并在它们的降解中合作。PDZ蛋白在维持细胞极性、形成细胞-细胞粘附连接和作为支架蛋白的多蛋白信号复合物的组织中起主要作用。它们被E6靶向可能导致细胞极性丧失和形态转化，与上皮-间充质转化相关，导致转化和癌变。这些E6蛋白结合PDZ结构域蛋白的能力与病毒的致癌潜力相关。来自betaPV的致癌HPV（例如HPV 8）的E6蛋白不编码PDZ结合基序。我们最近发现，PDZ结构域蛋白Syntenin-2在原代人表皮角质形成细胞（PHEK）中被HPV 8-E6转录下调。已知的HPV 16-E6 PDZ蛋白靶点Dlg、Scribble、Magi-1/-3、PSD 95和Mupp 1的mRNA水平未被HPV 8-E6改变。令人惊讶的是，HPV 16-E6也抑制了Syntenin-2的转录，但效率低于HPV 8-E6。这些结果表明Syntenin-2是第一个在mRNA水平上受HPV 8和HPV 16控制的PDZ结构域蛋白。shRNA介导的Syntenin-2敲低导致PHEK分化抑制和增殖能力增加。因此，我们假设，Syntenin-2基因表达的综合评价将确定皮肤稳态和角质形成细胞增殖和永生化的Syntenin-2的具体贡献。此外，了解高危型HPV 8型和16型控制Syntenin-2基因表达的调控机制可能至关重要，并可能为我们将来了解HPV发病机制提供进一步的方面。