All-trans retinoic acid induces anti-tumor effects via STAT3 signaling inhibition in oral squamous cell carcinoma and oral dysplasia.

Abstract

Oral squamous cell carcinoma (OSCC), which may arise from oral dysplasia, is one of the most prevalent cancers around the world. In recent years, all-trans retinoic acid (ATRA) has shown great potential in cancer treatment. However, the molecular mechanism for the anti-tumor effects of ATRA remains unclear. After treated with ATRA, inhibition of cell proliferation of OSCC and oral dysplasia cell lines, CAL27 and DOK, respectively, was analyzed by a Cell Counting Kit-8 (CCK8) assay. The cell cycle arrest, cell apoptosis induction, and PD-L1 expression level were measured by flow cytometry. A small molecular inhibitor was utilized to block STAT3 pathway, and the related proteins expression was measured by Western Blot. The present study demonstrated that ATRA inhibited cell proliferation at 5-75μmol/L, arrested cell cycle at S and G2-phase, induced apoptosis effect in OSCC, and oral dysplasia cell line, CAL27 and DOK, respectively. ATRA led to inhibition of p-STAT3, p-JAK2, increased the level of p-ERK, and significantly decreased the PD-L1 expression. Moreover, targeting STAT3 signaling increased (P<.001) the level of cleaved caspase-3 and effectively (P<.001) decreased the expression of cyclin A2 and PD-L1. The effect of ATRA on cell growth inhibition, apoptosis induction, and PD-L1 expression decrease was significantly (P<.05) enhanced after the STAT3 signaling blockade. These findings suggested that ATRA-induced anti-tumor effects and downregulated PD-L1 expression via STAT3 signaling inhibition in both OSCC and oral dysplasia.