PLEKHS1 Over-Expression is Associated with Metastases and Poor Outcomes in Papillary Thyroid Carcinoma.

Pleckstrin homology domain containing S1 (PLEKHS1) is a poorly characterized factor, although its promoter mutations were identified in human malignancies including thyroid carcinoma (TC). This study was designed to determine promoter hotspot mutations in papillary and anaplastic thyroid carcinomas (PTCs and ATCs) and to evaluate if expression influences clinical outcome. The promoter mutation was observed in 1/93 of PTCs and none of 18 ATCs in our cohort; however, expression was aberrantly up-regulated in TCs compared to adjacent non-tumorous thyroid tissues. ATC tumors, an undifferentiated TC, exhibited the highest expression. In both TCGA and present cohorts of PTCs, gene methylation density was inversely correlated with its mRNA expression and demethylation at the locus occurred at two CpGs. Higher expression was associated with lymph node and distant metastases, and shorter overall and disease-free survival in our cohort of PTC patients. Importantly, over-expression predicted shorter patient survival in PTCs lacking promoter mutations. Cellular experiments showed that over-expression enhanced AKT phosphorylation and invasiveness. Collectively, the gene demethylation causes its over-expression in PTCs. promotes aggressive behavior of TCs possibly by increasing AKT activity, and its over-expression predicts poor patient outcomes.