Human papillomavirus 16 oncoprotein regulates the translocation of β-catenin via the activation of epidermal growth factor receptor.
Human papillomavirus 16 oncoprotein regulates the translocation of β-catenin via the activation of epidermal growth factor receptor.
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DOI：
10.1002/cncr.29039
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发表时间：
2015-01-15
期刊：
影响因子：
6.2
通讯作者：
Chen, Zhuo Georgia
中科院分区：
文献类型：
--
作者：
Hu, Zhongliang;Mueller, Susan;Qian, Guoqing;Xu, Jing;Kim, Sungjin;Chen, Zhengjia;Jiang, Ning;Wang, Dongsheng;Zhang, Hongzheng;Saba, Nabil F.;Shin, Dong M.;Chen, Zhuo Georgia
关键词：
为了解高危型人乳头瘤病毒相关性口咽鳞状细胞癌早期和频繁淋巴结转移的机制，我们研究了β-catenin是否受人乳头瘤病毒癌基因蛋白调控并参与口咽鳞状细胞癌的转移。采用免疫组织化学方法检测p16、β-连环蛋白和表皮生长因子受体在口腔鳞状细胞癌中的表达。用免疫印迹法检测β-catenin在阳性和阴性头颈部鳞状细胞癌细胞系中的表达和亚细胞定位及活化情况。用HPV16E6siRNA检测HPV癌蛋白对β-连环蛋白易位的影响。厄洛替尼治疗证实了表皮生长因子受体参与β-连环蛋白转位。此外，还观察了HPV16E6/E7抑制后细胞的侵袭能力。结果显示，β-catenin的膜加权指数(WI)与p16阳性(p<；0.001)和淋巴结转移(p=0.026)呈负相关，而β-catenin的核染色与p16阳性的鳞癌(p<；0.001)呈负相关。细胞膜β-连环蛋白的低水平表达与无病生存和总存活率显著相关(P<；两个病例均为0.0001)。此外，表皮生长因子受体的膜WI值与p16表达呈负相关(p<；0.001)，与膜β-catenin呈正相关(p<；0.001)。我们的体外研究表明，抑制HPV16E6基因表达后，细胞的磷酸化表皮生长因子受体和核β-连环蛋白的表达减少，并且抑制了细胞的侵袭。我们的研究结果提示，HPV16E6介导了β-连环蛋白向细胞核的移位，这可能受激活的表皮生长因子受体的调节。
To understand the mechanism of frequent and early lymph node metastasis in high risk human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC), we investigated whether β-catenin is regulated by HPV oncoprotein and contributes to OPSCC metastasis. Expression levels of p16, β-catenin, and epidermal growth factor receptor (EGFR) were examined in OPSCC samples (n=208) by immunohistochemistry. Expression and subcellular localization of β-catenin and EGFR activation were also studied in HPV-positive and -negative head and neck SCC cell lines by Western blot analysis. HPV16 E6 siRNA was used to elucidate the effect of HPV oncoprotein on β-catenin translocation. The involvement of EGFR in β-catenin translocation was confirmed by treatment with erlotinib. Moreover, the invasive capacity was evaluated after HPV16 E6/E7 repression. Our results showed that membrane weighted index (WI) of β-catenin was inversely correlated with p16 positivity (p<0.001) and lymph node metastasis (p=0.026), while nuclear staining of β-catenin was associated with p16-positive OPSCC (p<0.001). A low level of membrane β-catenin expression was significantly associated with disease free and overall survival (p<0.0001 in both cases). Furthermore, the membrane WI of EGFR was inversely correlated with p16 positivity (p<0.001) and positively correlated with membrane β-catenin (p<0.001). Our in vitro study showed that HPV16 E6 repression led to reductions of phosphoEGFR, and nuclear β-catenin, which were also observed after erlotinib treatment, and inhibition of invasion. Our findings suggest that HPV16 E6 mediates the translocation of β-catenin to the nucleus, which may be regulated by activated EGFR.
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