MicroRNAs (miR) are small RNA molecules that shape the cell transcriptome and proteome through regulation of mRNA stability and translation. Here, we examined their function as determinants of cell resistance to complement-dependent cytotoxicity (CDC). To achieve this goal, we compared the expression of microRNAs between complement-resistant and -sensitive K562 leukemia, Raji lymphoma, and HCT-116 colorectal carcinoma cells. Global microRNA array analysis identified miR-150, miR-328, and miR-616 as regulators of CDC resistance. Inhibition of miR-150 reduced resistance, whereas inhibition of miR-328 or miR-616 enhanced cell resistance. Treatment of K562 cells with a sublytic dose of complement was shown to rapidly increase miR-150, miR-328, and miR-616 expression. Protein targets of these microRNAs were analyzed in K562 cells by mass spectrometry-based proteomics. Expression of the complement membrane regulatory proteins CD46 and CD59 was significantly enhanced after inhibition of miR-328 and miR-616. Enrichment of proteins of mitochondria, known target organelles in CDC, was observed after miR-150, miR-328, and miR-616 inhibition. In conclusion, miR-150, miR-328, and miR-616 regulate cell resistance to CDC by modifying the expression of the membrane complement regulators CD46 and CD59 and the response of the mitochondria to complement lytic attack. These microRNAs may be considered targets for intervention in complement-associated diseases and in anticancer, complement-based therapy.

中文翻译：

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MicroRNA影响补体调节因子的表达和线粒体活性，以调节细胞对补体依赖性细胞毒性的抵抗力。

MicroRNA（miR）是小的RNA分子，可通过调节mRNA的稳定性和翻译来塑造细胞的转录组和蛋白质组。在这里，我们检查了它们作为细胞对补体依赖性细胞毒性（CDC）抗性的决定因素的功能。为了实现此目标，我们比较了补体耐药和敏感的K562白血病，Raji淋巴瘤和HCT-116大肠癌细胞之间的microRNA表达。全球microRNA阵列分析确定了miR-150，miR-328和miR-616是CDC抗性的调节因子。抑制miR-150可降低耐药性，而抑制miR-328或miR-616可增强细胞耐药性。用消融剂量的补体处理K562细胞显示可快速增加miR-150，miR-328和miR-616的表达。通过基于质谱的蛋白质组学在K562细胞中分析了这些microRNA的蛋白质靶标。抑制miR-328和miR-616后，补体膜调节蛋白CD46和CD59的表达显着增强。抑制miR-150，miR-328和miR-616后，发现CDC中已知的靶细胞器线粒体蛋白质富集。总之，miR-150，miR-328和miR-616通过修饰膜补体调节剂CD46和CD59的表达以及线粒体对补体溶解攻击的反应来调节细胞对CDC的抗性。这些microRNA可能被视为干预补体相关疾病和抗癌补体疗法的靶标。抑制miR-328和miR-616后，补体膜调节蛋白CD46和CD59的表达显着增强。抑制miR-150，miR-328和miR-616后，发现CDC中已知的靶细胞器线粒体蛋白质富集。总之，miR-150，miR-328和miR-616通过修饰膜补体调节剂CD46和CD59的表达以及线粒体对补体溶解攻击的反应来调节细胞对CDC的抗性。这些microRNA可能被视为干预补体相关疾病和抗癌，基于补体的治疗的靶标。抑制miR-328和miR-616后，补体膜调节蛋白CD46和CD59的表达显着增强。抑制miR-150，miR-328和miR-616后，发现CDC中已知的靶细胞器线粒体蛋白质富集。总之，miR-150，miR-328和miR-616通过修饰膜补体调节剂CD46和CD59的表达以及线粒体对补体溶解攻击的反应来调节细胞对CDC的抗性。这些microRNA可能被视为干预补体相关疾病和抗癌补体疗法的靶标。miR-616和miR-616通过修饰膜补体调节剂CD46和CD59的表达以及线粒体对补体溶解攻击的反应来调节细胞对CDC的抗性。这些microRNA可能被视为干预补体相关疾病和抗癌，基于补体的治疗的靶标。miR-616和miR-616通过修饰膜补体调节剂CD46和CD59的表达以及线粒体对补体溶解攻击的反应来调节细胞对CDC的抗性。这些microRNA可能被视为干预补体相关疾病和抗癌，基于补体的治疗的靶标。