MicroRNAs are major post-transcriptional regulators responsible for the development of human cancers, including OSCC. The specific role of miR-619-5p in OSCC, however, is rarely reported. Cisplatin is one of the mostly applied chemotherapy drugs of OSCC. Nevertheless, drug resistance of cisplatin following the initial chemotherapy largely restricts its clinical benefits, and the mechanism of cisplatin resistance is unclear. This study intends to explore the biological function of miR-619-5p in the development of cisplatin resistance in OSCC cell lines and a xenograft model, as well as the potential molecular mechanism. Our results showed that miR-619-5p was down-regulated in OSCC samples and cisplatin-resistant OSCC cells. Ectopically expressed miR-619-5p inhibited proliferative, migratory and invasive abilities of OSCC cisplatin-resistant cells. The putative target gene ATXN3 was predicted by bioinformatic analysis and confirmed by dual-luciferase reporter assay. Importantly, ATXN3 was responsible for the regulatory effects of miR-619-5p on biological behaviors of cisplatin-resistant OSCC cells. Moreover, miR-619-5p mimics and ATXN3-siRNA significantly enhanced ATXN3 knockdown in both HN6/CDDPR and CAL27/CDDPR cells and inhibited expression of PI3K and AKT. In vivo evidences demonstrated that intratumoral injection of miR-619-5p agomir remarkably slowed down the growth of OSCC in xenograft mice. Collectively, microRNA-619-5p was the vital regulator for regulating cisplatin resistance of OSCC, which may be served as a potential therapeutic target.

中文翻译：

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miR-619-5p通过调节ATXN3参与口腔鳞状细胞癌顺铂耐药


MicroRNA 是主要的转录后调节因子，负责人类癌症（包括 OSCC）的发展。然而，miR-619-5p 在 OSCC 中的具体作用却很少报道。顺铂是口腔鳞癌应用最广泛的化疗药物之一。然而，初始化疗后顺铂的耐药很大程度上限制了其临床获益，且顺铂耐药的机制尚不清楚。本研究旨在探讨miR-619-5p在OSCC细胞系和异种移植模型顺铂耐药发展中的生物学功能及其潜在的分子机制。我们的结果表明，miR-619-5p 在 OSCC 样本和顺铂耐药 OSCC 细胞中下调。异位表达的 miR-619-5p 抑制 OSCC 顺铂耐药细胞的增殖、迁移和侵袭能力。通过生物信息学分析预测推定的靶基因ATXN3，并通过双荧光素酶报告基因测定证实。重要的是，ATXN3 负责 miR-619-5p 对顺铂耐药 OSCC 细胞生物学行为的调节作用。此外，miR-619-5p模拟物和ATXN3-siRNA显着增强HN6/CDDPR和CAL27/CDDPR细胞中ATXN3的敲低，并抑制PI3K和AKT的表达。体内证据表明，瘤内注射 miR-619-5p agomir 可显着减缓异种移植小鼠 OSCC 的生长。总的来说，microRNA-619-5p是调节OSCC顺铂耐药的重要调节因子，可能作为潜在的治疗靶点。