Correlation of Expression of Phosphorylated and Non-phosphorylated Yes-associated Protein with Clinicopathological Parameters in Esophageal Squamous Cell Carcinoma in a Korean Population

Yes-associated protein (YAP) is a nuclear downstream effector of the Hippo pathway, a regulator of cell growth. The phosphorylated form of YAP (pYAP), located in the cytoplasm, prevents cellular proliferation by spatially segregating YAP from the nucleus. This study aimed at investigating the relationships of pYAP and YAP with clinicopathological variables in esophageal squamous cell carcinoma (ESCC). Samples of ESCC from 142 patients were studied using immunohistochemistry for YAP, pYAP and Ki-67. In all cases of ESCC, higher nuclear expression of YAP was correlated with Ki-67 expression, tumor diameter, histological grade (1-2 versus 3), and pathological TNM stage (I versus II-IV) in univariate analyses (p=0.036, p=0.025, p=0.021, and p=0.033, respectively). Higher nuclear expression of YAP was associated with worse overall and disease-free survival (p=0.006 and p=0.008, respectively). Multivariate analysis showed higher nuclear expression of YAP to be an independent prognostic marker for overall survival (p=0.034). We observed a trend towards inverse correlation of cytoplasmic pYAP expression and histological grade (1-2 versus 3) (p=0.087). Our results suggest that YAP shifts from the nucleus to the cytoplasm as a consequence of phosphorylation, which occurs in the presence of high tumor cell density in the case of ESCC, and may be a potential indication of histological differentiation. Nuclear expression of YAP is correlated with tumor cell proliferation and is an independent predictor of worse prognosis of ESCC.