Clinical importance of PLA2R1 and RASSF9 in thyroid cancer and their inhibitory roles on the Wnt/β-catenin pathway and thyroid cancer cell malignant behaviors.

Thyroid cancer is a common malignant tumor with rising incidence worldwide. The purpose of this study was to explore key genes in thyroid cancer. The differentially expressed genes were analyzed according to GEO datasets. PLA2R1 and RASSF9 levels were confirmed by UALCAN and the Human Protein Atlas databases. The disease free survival and linear correlation were analyzed by GEPIA. ROC curve was generated according to The Cancer Genome Atlas (TCGA) database. The methylation level and immune infiltration were analyzed using GSCA platform. PLA2R1, RASSF9 and Wnt/β-catenin-related protein levels were detected by western blotting. Cell proliferation was assessed by 5-ethynyl-2'-deoxyuridine assay. Cell invasion and migration were evaluated by Transwell assay. There were 2 common differentially expressed genes (PLA2R1 and RASSF9) in thyroid cancer from GSE104005, GSE65144 and GSE53157 datasets. Decreased PLA2R1 and RASSF9 were associated with advanced stages and lower disease free survival. PLA2R1 and RASSF9 methylation levels were enhanced in thyroid cancer samples compared with normal samples. PLA2R1 methylation level was negatively correlated to its mRNA level. PLA2R1 and RASSF9 were related to immune infiltration in thyroid cancer. PLA2R1 and RASSF9 expression was associated with radioiodine resistance, and positively correlated to expression of iodide uptake-related factors. Multiple signaling pathways were involved in the action mechanisms of PLA2R1 and RASSF9, including the Wnt/β-catenin signaling. Overexpression of PLA2R1 and RASSF9 inhibited the activation of the Wnt/β-catenin pathway, proliferation, invasion, and migration in thyroid cancer cells. Collectively, PLA2R1 and RASSF9 are two key genes in thyroid cancer, which have potential diagnostic, prognostic, and anti-tumor effects in thyroid cancer.