The aim of this study is to understand the association of HPV infection and wnt-β-catenin self-renewal pathway in development of head and neck squamous cell carcinoma (HNSCC). For this reason, the molecular profiles (methylation/deletion/expression) of antagonists (SFRP1/2 and DKK1), agonists (FZD7 and LRP6) and effector protein β-catenin of the pathway were analyzed in HPV positive/negative oral epithelium at first, followed by its changes during development of the tumor along with correlations with different clinico-pathological parameters. HPV infection alone or in combination with tobacco habit could activate p- β-catenin expression in basal/parabasal layers of oral epithelium through high expression of FZD7 and significant down regulation of SFRP1/2 through promoter hypermethylation due to over expression of DNMT1 with ubiquitous down regulation of DKK1 and up-regulation of LRP6. This phenomenon has been seen in respective HPV positive and negative HNSCC tumors with additional deletion/microsatellite size alterations in the antagonists. Overall alterations (methylation/deletion) of SFRP1/2, DKK1 gradually increased from Group I (HPV-/Tobacco-) to Group IV(HPV+/Tobacco+) tumors, leading to the worst prognosis of the patients. Thus, the transmission of differentially activated wnt-β-catenin pathway from HPV positive/negative basal/parabasal layers of oral epithelium to HNSCC tumors determines differences in molecular pathogenesis of the disease.

本研究的目的是了解 HPV 感染和 wnt-β-catenin 自我更新途径在头颈部鳞状细胞癌 (HNSCC) 发展中的关联。为此，首先在 HPV 阳性/阴性口腔上皮中分析了拮抗剂（SFRP1/2 和 DKK1）、激动剂（FZD7 和 LRP6）和该途径的效应蛋白 β-连环蛋白的分子谱（甲基化/缺失/表达） ，其次是其在肿瘤发展过程中的变化以及与不同临床病理参数的相关性。HPV 感染单独或与烟草习惯结合可以通过 FZD7 的高表达和 SFRP1/2 通过启动子高甲基化的显着下调来激活口腔上皮基底/副基底层中 p-β-catenin 的表达，这是由于DKK1 的调节和 LRP6 的上调。这种现象已经在各自的 HPV 阳性和阴性 HNSCC 肿瘤中观察到，在拮抗剂中具有额外的缺失/微卫星大小改变。SFRP1/2、DKK1的整体改变（甲基化/缺失）从I组（HPV-/烟草-）到IV组（HPV+/烟草+）肿瘤逐渐增加，导致患者预后最差。因此，