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

Abstract 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 are potential CSCs. MicroRNAs (miRNAs) have emerged as crucial players in tumor development. However, their role in maintenance of OSCC stem cells remains unclear. Here we report that CD44highCD24low population within OSCC cells 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 stemness by stabilizing β-catenin with concomitant loss of E-cadherin and CD24. Interestingly, CD24 is 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. Using stably expressing miR-146a/CD24 OSCC cell lines, 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 regulate CSCs in OSCC through CD24-AKT-β-catenin axis. Highlights MiR-146a induces cancer stem cell characteristics in OSCC by targeting CD24 CD24 abrogates miR-146a mediated stemness via β-catenin degradation in non-CSCs Akt/Wnt pathway is critical for sustenance of miR-146a driven potential CSCs The miR-146a/CD24/AKT loop significantly alters tumorigenic ability in vivo