STC1 promotes paclitaxel resistance in oral squamous cell carcinoma by inhibiting oxidative stress via activating the JAK/STAT signaling pathway.

AIMS

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of the oral cavity, with chemoresistance is the greatest challenge in chemotherapeutic treatment. Stanniocalcin 1 (STC1) is correlated with tumor malignancy and chemoresistance in various cancers, but its role in OSCC paclitaxel (PTX) resistance remains elusive. This study aimed to clarify STC1's impact on OSCC PTX resistance and elucidate its underlying mechanism.

MATERIALS AND METHODS

The PTX-resistant OSCC cell line CAL-27/PTX was established by stepwise exposure to increasing PTX concentrations. Transcriptomic sequencing, CCK-8 assays, western blotting, RT-qPCR, lentiviral-mediated silencing or overexpression, reactive oxygen species (ROS) detection, and ELISA were used to assess STC1 expression and function. In vivo validation was conducted using both cell line-derived (CDX) and patient-derived xenograft (PDX) models.

KEY FINDINGS

The expression of STC1 was significantly increased in CAL-27/PTX cells and linked to cancer stem cell-like characteristics and epithelial-mesenchymal transition. Knockdown of STC1 expression suppresses tumor development. Mechanistically, STC1 activated the JAK/STAT signaling pathway, which mediated the upregulation of antioxidant genes (GPX4, FTH1, and SLC7A11) to attenuate PTX-induced oxidative stress. Additionally, STC1 promoted intercellular transfer of PTX resistance via a paracrine mechanism. In vivo, high STC1 expression mediated PTX resistance in both CDX and PDX tumor models.

SIGNIFICANCE

This study identifies the STC1-STAT3-SLC7A11 axis as a key regulator of resistance to oxidative stress in OSCC, highlighting STC1 as a promising therapeutic target to overcome chemoresistance and improve outcomes in PTX-based therapies.