BACKGROUND Chemoresistance remains a critical event that accounts for colorectal cancer (CRC) lethality. The aim of this study is to explore the ability of dichloroacetate (DCA) to increase chemosensitivity in CRC and the molecular mechanisms involved. METHODS The effects of combination treatment of DCA and oxaliplatin (L-OHP) were analysed both in vitro and in vivo. The DCA-responsive proteins in AMPK pathway were enriched using proteomic profiling technology. The effect of DCA on CAB39-AMPK signal pathway was analysed. In addition, miRNA expression profiles after DCA treatment were determined. The DCA-responsive miRNAs that target CAB39 were assayed. Alterations of CAB39 and miR-107 expression were performed both in vitro and on xenograft models to identify miR-107 that targets CAB39-AMPK-mTOR signalling pathway. RESULTS DCA increased L-OHP chemosensitivity both in vivo and in vitro. DCA could upregulate CAB39 expression, which activates the AMPK/mTOR signalling pathway. CAB39 was confirmed to be a direct target of miR-107 regulated by DCA. Alterations of miR-107 expression were correlated with chemoresistance development in CRC both in vitro and in vivo. CONCLUSION These findings suggest that the miR-107 induces chemoresistance through CAB39-AMPK-mTOR pathway in CRC cells, thus providing a promising target for overcoming chemoresistance in CRC.

中文翻译：

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MiR-107通过靶向钙结合蛋白39赋予大肠癌化学耐药性。

背景化学抗性仍然是导致结直肠癌（CRC）致死性的关键事件。这项研究的目的是探索二氯乙酸盐（DCA）增强CRC的化学敏感性的能力以及涉及的分子机制。方法在体内和体外分析DCA和奥沙利铂（L-OHP）联合治疗的效果。AMPK通路中的DCA反应蛋白使用蛋白质组分析技术进行了富集。分析了DCA对CAB39-AMPK信号通路的影响。另外，确定了DCA处理后的miRNA表达谱。分析了靶向CAB39的DCA反应性miRNA。在体外和异种移植模型上均进行了CAB39和miR-107表达的改变，以鉴定靶向CAB39-AMPK-mTOR信号通路的miR-107。结果DCA在体内和体外均可提高L-OHP的化学敏感性。DCA可能上调CAB39表达，从而激活AMPK / mTOR信号通路。证实CAB39是DCA调控的miR-107的直接靶标。miR-107表达的改变与体外和体内CRC的化学抗药性发展相关。结论这些发现表明，miR-107通过CAB39-AMPK-mTOR途径诱导CRC细胞的化学耐药性，从而为克服CRC的化学耐药性提供了有希望的靶点。miR-107表达的改变与体外和体内CRC的化学抗药性发展相关。结论这些发现表明，miR-107通过CAB39-AMPK-mTOR途径诱导CRC细胞的化学耐药性，从而为克服CRC的化学耐药性提供了有希望的靶点。miR-107表达的改变与体外和体内CRC的化学抗药性发展相关。结论这些发现表明，miR-107通过CAB39-AMPK-mTOR途径诱导CRC细胞的化学耐药性，从而为克服CRC的化学耐药性提供了有希望的靶点。