Yes-associated protein (YAP) plays oncogenic roles in human sporadic colorectal adenomas.

Abstract

The role of Hippo-YAP in human colorectal cancer (CRC) presents contradictory results. We examined the function of YAP in the early stages of CRC by quantitatively measuring the expression of phospho-YAPS127 (p-YAP) and five APC-related proteins in 145 sporadic adenomas from the Tennessee Colorectal Polyp Study, conducting APC sequencing for 114 adenomas, and analyzing YAP-correlated cancer pathways using gene expression data from 326 adenomas obtained from Gene Expression Omnibus. The p-YAP expression was significantly correlated with YAP expression (r=0.53, P<0.0001) and nuclear β-catenin (r=0.26, P=0.0018) in adenoma tissues. Both p-YAP and nuclear β-catenin were associated with APC mutations (P=0.05). A strong association was observed between p-YAP overexpression and advanced adenoma odds (OR=12.62, 95% CI=4.57-34.86, P trend<0.001), which persisted after adjusting for covariates and biomarkers (OR=12.31, 95% CI=3.78-40.10, P trend<0.0001). P-YAP exhibited a sensitivity of 77.4% and specificity of 78.2% in defining advanced vs. non-advanced adenomas. Additionally, synergistic interaction was noted between p-YAP positivity and nuclear β-catenin on advanced adenomas (OR=16.82, 95% CI=4.41-64.08, P<0.0001). YAP-correlated genes were significantly enriched in autophagy, unfolded protein response, and sirtuin pathways showing predominantly pro-tumorigenic alterations. Collectively, YAP plays an oncogenic role in interacting with Wnt as well as other cancer pathways within human sporadic adenomas. P-YAP could be a potential biomarker for human high-risk sporadic adenomas.