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

ABSTRACT

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: The present study demonstrated that ATRA inhibited cell proliferation at 5-75 µmol/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. CONCLUSION: These findings suggested that ATRA-induced anti-tumor effects and downregulated PD-L1 expression via STAT3 signaling inhibition in both OSCC and oral dysplasia.