Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat 382355, India.
Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat 382355, India.
Mol Pharm. 2021 Aug 2;18(8):3010-3025. doi: 10.1021/acs.molpharmaceut.1c00213. Epub 2021 Jun 28.
Cisplatin resistance is one of the major concerns in the treatment of oral squamous cell carcinoma (OSCC). Accumulating evidence suggests microRNA (miRNA) dysregulation as one of the mediators of chemoresistance. Toward this, our previous study revealed the role of exosomal microRNA-155 (miR-155) in cisplatin resistance via downregulation of FOXO3a, a direct target of miR-155, and induction of epithelial-to-mesenchymal transition in OSCC. In the present study, we demonstrate the therapeutic potential of miR-155 inhibitor-laden exosomes in the sensitization of a cisplatin-resistant (cis) OSCC 3D tumor spheroid and xenograft mouse model. The cis OSSC 3D tumor spheroid model recapitulated the hallmarks of solid tumors such as enhanced hypoxia, reactive oxygen species, and secretory vascular endothelial growth factor. Further treatment with miR-155 inhibitor-loaded exosomes showed the upregulation of FOXO3a and induction of the mesenchymal-to-epithelial transition with improved sensitization to cisplatin in cis tumor spheroids and xenograft mouse model. Moreover, the exosomal miR-155 inhibitor suppressed the stem-cell-like property as well as drug efflux transporter protein expression in cisplatin-resistant tumors. Taken together, our findings, for the first time, established that the miR-155 inhibitor-loaded exosomes reverse chemoresistance in oral cancer, thereby providing an alternative therapeutic strategy for the management of refractory oral cancer patients.
顺铂耐药性是口腔鳞状细胞癌（OSCC）治疗中的主要关注点之一。越来越多的证据表明，miRNA（miRNA）失调是化疗耐药性的介导因素之一。为此，我们之前的研究表明，外泌体 microRNA-155（miR-155）通过下调 miR-155 的直接靶标 FOXO3a 以及诱导 OSCC 中的上皮-间充质转化，在顺铂耐药中发挥作用。在本研究中，我们证明了 miR-155 抑制剂载外泌体在顺铂耐药（cis）OSCC 3D 肿瘤球体和异种移植小鼠模型中的增敏作用。cis OSCC 3D 肿瘤球体模型再现了实体瘤的特征，如增强的缺氧、活性氧和分泌的血管内皮生长因子。进一步用 miR-155 抑制剂载外泌体处理显示，FOXO3a 的上调和间充质-上皮转化的诱导，改善了 cis 肿瘤球体和异种移植小鼠模型中对顺铂的敏感性。此外，外泌体 miR-155 抑制剂抑制了 cis 耐药肿瘤中的干细胞样特性和药物外排转运蛋白表达。总之，我们的研究结果首次证实，miR-155 抑制剂载外泌体逆转了口腔癌的化疗耐药性，从而为治疗难治性口腔癌患者提供了一种替代治疗策略。
