The WT1 protein molecule drives the proliferation and metastasis of anaplastic thyroid carcinoma through the EMT...

Anaplastic thyroid cancer (ATC) is a highly malignant and aggressive tumor, and previous studies have demonstrated its association with epithelial-mesenchymal transition (EMT). However, the specific protein targets remain unknown. In this study, we integrated multi-omics data and molecular experiments to reveal the crucial role of WT1 (Wilms' tumor 1 protein) as a core biomolecule in ATC. We screened up-regulated genes that were highly correlated with EMT through differentially expressed gene (DEG) analysis, weighted gene co-expression network (WGCNA), and machine-learning algorithms (LASSO/SVM-RFE). Notably, the area under the receiver operating characterization curve (AUC) for subjects with WT1 reached 0.968. Functional experiments confirmed that the knockdown of WT1 significantly inhibited the proliferation (CCK-8 assay), migration (scratch assay), and invasion (Transwell assay) of BHT101 and CAL-62 cells, and reversed the EMT phenotype by down-regulating the mesenchymal markers N-cadherin and Vimentin, while up-regulating the epithelial marker E-cadherin. Mechanistic studies showed that WT1 drives the EMT process by activating the PI3K/AKT signaling pathway, enhancing the p-AKT/AKT protein ratio. Additionally, this study further confirmed that WT1 promotes tumor growth using a subcutaneous xenograft model in nude mice, this work is the first to identify WT1 protein as a key driver of EMT in ATC.