Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Mol Carcinog. 2019 Dec;58(12):2181-2192. doi: 10.1002/mc.23107. Epub 2019 Aug 29.
Chemoresistance is the primary cause of chemotherapy failure. Compelling evidence shows that micro RNAs (miRNAs) contribute to reprogram cancer cells toward a resistant phenotype. We investigate the role of miRNAs in the response to acute treatment with 5-FU in colon cancer-resistant cells. We performed a global gene expression profile for the entire miRNA genome and found a change in the expression of four miRNAs following acute treatment with 5-FU. Among them, we focused on miR-210-3p, previously described as a key regulator of DNA damage repair mechanisms and mitochondrial metabolism. We show that miR-210-3p downregulation enables resistant cells to counteract the toxic effect of the drug increasing the expression of RAD-52 protein, responsible for DNA damage repair. Moreover, miR-210-3p downregulation enhances oxidative phosphorylation (OXPHOS), increasing the expression levels of succinate dehydrogenase subunits D, decreasing intracellular succinate levels and inhibiting HIF-1α expression. Altogether, these adaptations lead to increased cells survival following drug exposure. These evidence suggest that miR-210-3p downregulation following 5-FU sustains DNA damage repair and metabolic adaptation to counteract drug treatment.
化学耐药性是化疗失败的主要原因。有强有力的证据表明，microRNAs（miRNAs）有助于重新编程癌细胞，使其向耐药表型发展。我们研究了 miRNAs 在结肠癌耐药细胞对 5-FU 急性治疗反应中的作用。我们对整个 miRNA 基因组进行了全基因组基因表达谱分析，发现 5-FU 急性处理后四种 miRNAs 的表达发生了变化。其中，我们重点关注 miR-210-3p，先前被描述为 DNA 损伤修复机制和线粒体代谢的关键调节因子。我们表明，miR-210-3p 的下调使耐药细胞能够抵抗药物的毒性作用，增加 RAD-52 蛋白的表达，RAD-52 蛋白负责 DNA 损伤修复。此外，miR-210-3p 的下调增强了氧化磷酸化（OXPHOS），增加了琥珀酸脱氢酶亚基 D 的表达水平，降低了细胞内琥珀酸水平，并抑制了 HIF-1α 的表达。总之，这些适应导致药物暴露后细胞存活增加。这些证据表明，5-FU 后 miR-210-3p 的下调维持了 DNA 损伤修复和代谢适应，以抵抗药物治疗。
