TGFβ induces stemness through non-canonical AKT-FOXO3a axis in oral squamous cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Cancer Stem Cell Research

Background:

• FOXO3a is recognized as a tumor suppressor but has a complex role in cancer stem cells (CSCs).
• CSCs drive tumor initiation, chemo-resistance, and recurrence in cancers like oral squamous cell carcinoma (OSCC).
• The non-canonical transforming growth factor beta (TGFβ) pathway's role in OSCC stemness requires further elucidation.

Purpose of the Study:

• To investigate the role of FOXO3a in regulating OSCC stemness.
• To explore the involvement of a non-canonical TGFβ pathway in this regulation.
• To understand the interplay between TGFβ, FOXO3a, and CSC properties in OSCC.

Main Methods:

• Immunohistochemistry and western blot were used to assess FOXO3a expression in OSCC tissues and cell lines.
• Stable cell lines with altered FOXO3a expression were created using lentiviruses.
• In vitro and in vivo experiments evaluated FOXO3a's impact on stem-cell-like properties, alongside TGFβ's effects on FOXO3a.

Main Results:

• FOXO3a expression was widespread in OSCC and inversely correlated with stemness.
• TGFβ abolished FOXO3a's regulatory function via phosphorylation, nuclear exclusion, and degradation through a non-Smad pathway.
• The non-Smad AKT-FOXO3a axis was identified as crucial for TGFβ-mediated regulation of CSC stemness.

Conclusions:

• TGFβ promotes OSCC stemness by activating the non-canonical AKT-FOXO3a pathway.
• This study elucidates a key mechanism underlying CSC regulation in OSCC.
• The findings suggest the AKT-FOXO3a axis as a potential therapeutic target for CSC elimination.