TCF4-driven cathepsin S promotes papillary thyroid carcinoma via PI3K/AKT/mTOR.

Papillary thyroid carcinoma (PTC) usually has a good prognosis, but a subset of patients develops lymph node metastasis, radioiodine resistance and recurrence, and lacks effective molecular biomarkers and therapeutic targets. Cathepsin S (CTSS), a lysosomal cysteine protease, has been implicated in several malignancies, yet its role and regulation in PTC remain unclear. We integrated GEO and TCGA-THCA datasets with eQTL-based genetic instrument analyses to screen PTC-related genes and evaluate their association with clinicopathological features and DFS. CTSS expression was examined in clinical tissues and cell lines by immunohistochemistry, qRT-PCR and Western blotting. Gain- and loss-of-function models were used to assess the effects of CTSS on PTC cell proliferation, colony formation, migration, apoptosis and nude-mouse tumor growth. RNA-seq, TCGA pathway-score correlation analysis were used to explore downstream pathways, and transcriptional regulation was investigated by in silico prediction, ChIP-qPCR and dual-luciferase assays. CTSS emerged as a candidate gene associated with PTC occurrence, lymph node metastasis and shorter DFS. CTSS was markedly upregulated in PTC tissues and cell lines. Functionally, CTSS knockdown suppressed proliferation and migration/invasion and promoted apoptosis, whereas CTSS overexpression enhanced malignant phenotypes in the examined PTC cell models. CTSS expression was associated with activation of the PI3K/AKT/mTOR pathway, and CTSS inhibition attenuated pathway activation and tumor growth. TCF4 bound the CTSS promoter, increased CTSS transcription, and TCF4 knockdown reduced CTSS expression and PI3K/AKT/mTOR pathway activity. These findings suggest that CTSS promotes malignant phenotypes in PTC and is associated with PI3K/AKT/mTOR activation, while TCF4 may contribute to CTSS transcriptional regulation.