The study was focused on YAP expression patterns in head and neck squamous cell carcinoma and oral squamous cell carcinoma. Indexed YAP expression correlated with HNSCC tissue grade, site, and nodal metastasis through univariate analysis. Similarly, the analysis of OSCC tissues indicated a significant association of indexed YAP cytoplasmic expression with nodal metastasis. The clinical indicators, organ, differentiation grade and nodal metastasis were significantly correlated to the index of YAP staining. The index of YAP expression was elevated in well-differentiated HNSCC and diminished in higher grade HNSCC. This inverse correlation of YAP and HNSCC differentiation status differed from reports in liver cancer 
, but was similar to that found in breast cancer 
. It implied the possible correlations between YAP cytoplasmic expression and these variables. But, regardless of HNSCC tumor grade, YAP expression was markedly higher at the tumor margins. Although we do not understand the apparent correlation of tumor differentiation status and YAP expression observed, the association with nodal metastasis implied the migration ability of YAP, consistent with previous reports 
. In breast cancer, as well as HNSCC, YAP expression contributed to the migration ability of tumor cells 
We sought to resolve this discrepancy in indexed YAP expression with decreasing stage yet association with metastasis. We observed YAP nuclear expression diminished with increasing clinical stage. However, cytoplasmic YAP indexed expression increased with incidence of HNCC nodal metastasis. A previous report of cytoplasmic YAP localization suggested a proliferative advantage in HNSCC 
. The liver has elevated cytoplasmic YAP expression in poorly-differentiated carcinoma 
. However, in benign tissues, YAP was more frequently expressed in the suprabasal cells as well as basal cells compared to parabasal cells, whose differentiation level lies between the former two types of cells. The results implied no correlation between p63, a basal cell marker, and YAP. However, we identified the inversed expression patterns of YAP and p63 in some specific phenotypes: 1) P63 was expressed in the parabasal cells of benign tissues in which YAP was not expressed () 
. 2) P63 expression in poorly-differentiated HNSCC had little to no YAP expression ( and ). 3) Finally, YAP expression in benign suprabasal cells and well-differentiated HNSCC had little expression of p63 (). The observed inverse expression of p63 and YAP was supported by the report that YAP expression mediates p63 degradation 
. Yet, at the tumor's invasive front, p63 and YAP were both expressed.
The specific localization of YAP in cells at the tumor margins () and association with nodal metastasis initiated our studies on its role in metastatic progression. Based on mechanisms of metastatic progression that include individual cell migration and collective cell movement, we tested if YAP expression correlated with EMT or contact inhibition, respectively. Recently the ligand of epidermal growth factor receptor, amphiregulin, was reported to contribute to the proliferation and migration function of YAP in MCF10A 
. YAP over expression in MCF10A, a breast non-transform cell line, can cause EMT 
. Thus far, the role of YAP in EMT has been carried out in MCF10A, which does not endogenously express YAP. Thus, we used Fadu and SCC-25 cells, common HNSCC cell lines that expresses YAP. However, traditional markers of EMT progression were not altered by YAP knockdown. (, ). Interestingly, in cell culture, greater YAP expression was found on the edges of cell clusters 
. The contact inhibition function was first described in organ size control research. The over expression of YAP lead to liver size expansion, resulted from unrestricted cell proliferation 
. Thus, YAP expression in HNSCC may function as a means of sensing tissue/tumor size at the leading edge of tumor margins.
The expression of YAP in carcinoma tissues, compared to benign or benign adjacent tissues was dramatic. Hyperplastic tissues, such as papillomas, were found to have elevated YAP expression. In further examination of YAP expression in leukoplakia, a precancerous disease with a 10% chance to become OSCC, we found it was similar to benign tissue (). The concept of field cancerization, was initially proposed in HNSCC, to describe changes in epithelial cells adjacent to the cancer. Some of these changes in the non-transformed cells were associated with genetic alteration and could not be considered benign tissue. We found YAP was over-expressed in malignant cells of HNSCC as well as associated endothelia and fibroblasts. Similar YAP expression was not observed in parallel benign and precancerous tissues. On the whole expression levels of benign tissues or hyperplastic tissues appeared lower compared to that of carcinoma tissues. Thus, YAP expression can serve as a marker to distinguish pre-malignant and malignant progression of HNSCC in tissue sections that may have otherwise ambiguous tumor margins. Currently, histologic cues and p63 expression help determine margins of HNSCC. The additional use of YAP expression may benefit the verification of histological low-grade HNSCC.