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

人乳头瘤病毒（HPV）与上皮性癌症的发生有关，而高风险的人乳头瘤病毒属（alphaPV）已被证明是宫颈癌的必要致病因素。人乳头瘤病毒属（betaPV）的HPV类型与皮肤肿瘤的发展有关，特别是鳞状细胞癌（SCC）和光化性角化病。高风险α - pv（例如HPV16）的E6蛋白的特点是存在PDZ结合基序，通过该基序，它们与许多细胞中含有PDZ结构域的底物相互作用并协同降解。PDZ蛋白在维持细胞极性、形成细胞-细胞粘附连接以及作为支架蛋白的多蛋白信号复合物的组织中发挥重要作用。它们被E6靶向可能导致细胞极性丧失和形态转换，与上皮-间质转化相关，从而导致转化和致癌。这些E6蛋白与PDZ结构域蛋白结合的能力与病毒的致癌潜能相关。来自betaPV的致癌HPV的E6蛋白（例如HPV8）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HPV8-E6转录下调。已知HPV16-E6 PDZ蛋白靶点Dlg、Scribble、Magi-1/-3、PSD95和Mupp1的mRNA水平未受HPV8-E6的影响。令人惊讶的是，HPV16-E6也抑制Syntenin-2的转录，但效率低于HPV8-E6。这些结果表明Syntenin-2是第一个在mRNA水平上受HPV8和HPV16控制的pdz结构域蛋白。ShRNA介导的Syntenin-2的敲除导致PHEK的分化抑制和增殖能力增加。因此，我们假设对Syntenin-2基因表达的综合评估将确定Syntenin-2在皮肤稳态和角化细胞增殖和永生中的具体贡献。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，并可能为我们未来对HPV发病机制的理解提供进一步的方面。

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.