The Hippo component YAP localizes in the nucleus of human papilloma virus positive oropharyngeal squamous cell carcinoma

Abstract

BackgroundHPV 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.MethodsMolecular 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.ResultsThis 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.ConclusionOur 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.

WITHDRAWN: Interplay between cancer cells and M2 macrophages is necessary for miR-550a-3-5p down-regulation-mediated HPV-positive OSCC progression

“…However, there are also non-canonical pathways that promote nucleus-translocation of YAP/TAZ, and thus stimulate its transcriptional activities, through which YAP/TAZ plays important tumor-promoting roles in a number of cancers (53). Several studies have also showed that aberrant YAP accumulation in the nucleus of cancer cells was found in both cervical cancer and HPV-positive OSCC, and HPV-positive patients with higher YAP levels usually had a more advanced stage (54)(55)(56). Moreover, Webb Strickland and colleagues have reported that E6 oncoprotein could associate with cellular PDZ domain proteins to promote the nuclear localization of YAP (57).…”

WITHDRAWN: Interplay between cancer cells and M2 macrophages is necessary for miR-550a-3-5p down-regulation-mediated HPV-positive OSCC progression

“…Several studies have also showed that aberrant YAP accumulation in the nucleus of cancer cells was found in both cervical cancer and HPV-positive OSCC, and HPV-positive patients with higher YAP levels usually had a more advanced stage (60)(61)(62). Moreover, Webb Strickland and colleagues have reported that E6 oncoprotein could associate with cellular PDZ domain proteins to promote the nuclear localization of YAP (63).…”

Hippo Pathway and YAP Signaling Alterations in Squamous Cancer of the Head and Neck

“…The PI3K-PDK1 pathway integrates signals from fibronectin, LPA, GPCR receptors and EGFR [68]. Interestingly, despite the fact that nuclear YAP localization has been described in oropharyngeal HPV positive tumors [89], Hippo pathway alterations and in particular FAT1 inactivation or YAP amplification are not frequent events in HPV positive HNSCC [10] (Figure 3). Although further research into the role of the Hippo-YAP pathway in this tumor subtype is needed, it is tempting to speculate that other mechanisms might lead to YAP activation.…”