PRJNA565245
TGFß Induces Stemness through Non-canonical AKT-FOXO3a Axis in Oral Squamous Cell Carcinoma
Background:FOXO3a has been widely regarded as a tumor suppressor. It also plays a paradoxical role in regulating the cancer stem cells(CSCs), responsible for tumor-initiation, chemo-resistance, and recurrence in various solid tumors, including oral squamous cell carcinoma (OSCC).This study aims to uncover the role of FOXO3a and its importance for a non-canonical pathway of TGFß in regulating the OSCC stemness.Methods: We identified FOXO3a expression in OSCC tissues and cell lines. The correlation between FOXO3a and stemness was evaluated. The effects of FOXO3a on stem-cell like properties in OSCC was also evaluated. Further we also explored the effect of TGFß on FOXO3a with respect to its expression and function.Findings: Our findings suggest that FOXO3a was widely expressed and negatively correlated with the stemness in OSCC. This regulation can be abolished by TGFß through phosphorylation, nuclear exclusion, and degradation in the non-Smad pathway. We also observed that non-Smad AKT-FOXO3a axis is essential to regulate stemness of CSCs by TGFß.Interpretation: TGFß induces stemness through non-canonical AKT-FOXO3a axis in OSCC. Our study provides a foundation to understand the mechanism of CSCs and a possible therapeutic target to eliminate CSCs.