Ghuwalewala Sangeeta, Ghatak Dishari, Das Sumit, Roy Stuti, Das Pijush, Butti Ramesh, Gorain Mahadeo, Nath Somsubhra, Kundu Gopal C, Roychoudhury Susanta
Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology, Kolkata, India.
Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science (NCCS), Pune, India.
Front Oncol. 2021 Oct 12;11:651692. doi: 10.3389/fonc.2021.651692. eCollection 2021.
CD44CD24 population has been previously reported as cancer stem cells (CSCs) in Oral Squamous Cell Carcinoma (OSCC). Increasing evidence suggests potential involvement of microRNA (miRNA) network in modulation of CSC properties. MiRNAs have thus emerged as crucial players in tumor development and maintenance. However, their role in maintenance of OSCC stem cells remains unclear. Here we report an elevated expression of miR-146a in the CD44CD24 population within OSCC cells and primary HNSCC tumors. Moreover, over-expression of miR-146a results in enhanced stemness phenotype by augmenting the CD44CD24 population. We demonstrate that miR-146a stabilizes 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 . 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 CSCs in OSCC through CD24-AKT-β-catenin axis.
CD44CD24细胞群先前已被报道为口腔鳞状细胞癌（OSCC）中的癌症干细胞（CSC）。越来越多的证据表明，微小RNA（miRNA）网络可能参与了CSC特性的调节。因此，miRNA已成为肿瘤发生和维持过程中的关键因素。然而，它们在维持OSCC干细胞中的作用仍不清楚。在此，我们报告了OSCC细胞和原发性头颈部鳞状细胞癌（HNSCC）肿瘤中CD44CD24细胞群中miR-146a的表达升高。此外，miR-146a的过表达通过增加CD44CD24细胞群导致干性表型增强。我们证明，miR-146a使β-连环蛋白稳定，同时E-钙黏蛋白和CD24丢失。有趣的是，CD24被确定为miR-146a的一个新的功能靶点，CD24的异位表达消除了miR-146a驱动的潜在CSC表型。机制分析表明，较高的CD24水平抑制AKT磷酸化，导致β-连环蛋白降解。使用稳定表达miR-146a/CD24的OSCC细胞系，我们还验证了miR-146a/CD24/AKT环显著改变致瘤能力。此外，我们证实β-连环蛋白可反式激活miR-146a，从而形成一个有助于干细胞维持的正反馈环。总的来说，我们的研究表明，miR-146a通过CD24-AKT-β-连环蛋白轴调节OSCC中的CSC。
