MiR-146a-dependent regulation of CD24/AKT/β-catenin axis drives stem cell phenotype in oral cancer

Cancer stem cells (CSCs) are known to potentiate tumor initiation and maintenance in oral squamous cell carcinoma (OSCC). Increasing evidences suggest that CD44highCD24low population in OSCC exhibit CSC-like characteristics. The role of mi-RNAs in maintenance of oral CSCs has remained unclear. Here we report that CD44highCD24low population within OSCC cell lines and primary HNSCC tumors have an elevated expression of miR-146a. Moreover, over-expression of miR-146a results in enhanced stemness phenotype by augmenting CD44highCD24low population. We demonstrate that miR-146a induces CSC property by stabilizing β-catenin with concomitant loss of E-cadherin and CD24. Interestingly, CD24 has been identified as a novel functional target of miR-146a and ectopic expression of CD24 abrogates miR-146a driven potential CSC phenotype. Mechanistic analysis reveals that higher CD24 levels inhibit AKT phosphorylation leading to β-catenin degradation in non-CSCs. We also validate that the miR-146a/CD24/AKT loop significantly alters tumorigenic ability in vivo. Furthermore, we confirmed that β-catenin trans-activates miR-146a, thereby forming a positive feedback loop contributing to stem cell maintenance. Collectively, our study demonstrates that miR-146a regulates CSC-driven properties in OSCC through CD24-AKT-β-catenin axis.