The Hippo component YAP localizes in the nucleus of human papilloma virus positive oropharyngeal squamous cell carcinoma.
The Hippo component YAP localizes in the nucleus of human papilloma virus positive oropharyngeal squamous cell carcinoma.
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DOI：
10.1186/s40463-017-0187-1
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发表时间：
2017-02-22
期刊：
影响因子：
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通讯作者：
Hart RD
中科院分区：
文献类型：
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作者：
Alzahrani F;Clattenburg L;Muruganandan S;Bullock M;MacIsaac K;Wigerius M;Williams BA;Graham ME;Rigby MH;Trites JR;Taylor SM;Sinal CJ;Fawcett JP;Hart RD
HPV感染导致宫颈癌，部分原因是通过HPV E6癌蛋白介导Scribble的降解。最近，Scribble已被证明是Hippo信号级联的重要调节因子。Hippo通路的失调诱导了异常的细胞转化，上皮细胞向间充质细胞转化，从而促进了癌性进展。鉴于最近口咽HPV鳞状细胞癌的上升，我们试图确定Hippo信号成分是否与口咽鳞状细胞癌有关。分子和细胞技术包括免疫沉淀、Western blotting和免疫细胞化学，用于鉴定关键的Hippo通路效应物Yes-Associated Protein （YAP）1。采集CO2激光切除的口咽组织，用YAP1抗体检测HPV阳性OPSCC组织的肿瘤和癌前区域。本研究揭示了Scribble结合蛋白一氧化氮合酶1适配蛋白（NOS1AP）与YAP形成复合物。此外，NOS1APa和NOS1APc亚型与激活和非激活的YAP表现出不同的关联，并影响细胞增殖。与OPSCC HPV肿瘤中Hippo信号不受调节一致，我们在HPV阳性的OPSCC中看到Scribble的脱位和YAP1的核积累增加。我们的初步数据表明，NOS1AP亚型与YAP1存在差异关联，这与我们之前的研究结果一起预测，YAP1的缺失会增强细胞转化。此外，YAP1在hpv阳性OPSCC的细胞核中高度积累，这意味着Hippo信号通路和可能的NOS1AP表达在OPSCC中被去调控。进一步的研究将有助于确定NOS1AP异构体、Scribble和Hippo成分是否将成为OPSCC肿瘤生物学中有用的生物标志物。
HPV infection causes cervical cancer, mediated in part by the degradation of Scribble via the HPV E6 oncoprotein. Recently, Scribble has been shown to be an important regulator of the Hippo signaling cascade. Deregulation of the Hippo pathway induces an abnormal cellular transformation, epithelial to mesenchymal transition, which promotes oncogenic progression. Given the recent rise in oropharyngeal HPV squamous cell carcinoma we sought to determine if Hippo signaling components are implicated in oropharyngeal squamous cell carcinoma. Molecular and cellular techniques including immunoprecipiations, Western blotting and immunocytochemistry were used to identify the key Hippo pathway effector Yes-Associated Protein (YAP)1. Oropharyngeal tissue was collected from CO2 laser resections, and probed with YAP1 antibody in tumor and pre-malignant regions of HPV positive OPSCC tissue. This study reveals that the Scribble binding protein Nitric Oxide Synthase 1 Adaptor Protein (NOS1AP) forms a complex with YAP. Further, the NOS1APa and NOS1APc isoforms show differential association with activated and non-activated YAP, and impact cellular proliferation. Consistent with deregulated Hippo signaling in OPSCC HPV tumors, we see a delocalization of Scribble and increased nuclear accumulation of YAP1 in an HPV-positive OPSCC. Our preliminary data indicates that NOS1AP isoforms differentially associate with YAP1, which, together with our previous findings, predicts that loss of YAP1 enhances cellular transformation. Moreover, YAP1 is highly accumulated in the nucleus of HPV-positive OPSCC, implying that Hippo signaling and possibly NOS1AP expression are de-regulated in OPSCC. Further studies will help determine if NOS1AP isoforms, Scribble and Hippo components will be useful biomarkers in OPSCC tumor biology.