Mitochondrial miRNA Determines Chemoresistance by Reprogramming Metabolism and Regulating Mitochondrial Transcription.
Mitochondrial miRNA Determines Chemoresistance by Reprogramming Metabolism and Regulating Mitochondrial Transcription.
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线粒体 miRNA 通过重编程代谢和调节线粒体转录来确定化疗耐药性
DOI：
10.1158/0008-5472.can-18-2505
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发表时间：
2019-03-15
期刊：
影响因子：
11.2
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Fan S;Tian T;Chen W;Lv X;Lei X;Zhang H;Sun S;Cai L;Pan G;He L;Ou Z;Lin X;Wang X;Perez MF;Tu Z;Ferrone S;Tannous BA;Li J
从细胞核易位到线粒体的 MicroRNA (miRNA) 被称为线粒体 microRNA (mitomiR)。 mitomiR 已被证明可以调节线粒体基因组的翻译活性，但它们在线粒体 DNA (mtDNA) 转录中的作用仍有待确定。在这里，我们报道 mitomiR-2392 通过下调氧化磷酸化 (OXPHOS) 和上调糖酵解来重新编程代谢，从而调节舌鳞状细胞癌 (TSCC) 细胞的化疗耐药性。这些效应是通过 mitomiR-2392 部分抑制 mtDNA 转录来介导的，而不是通过翻译调节来介导。这种抑制需要特定的 miRNA-mtDNA 碱基配对和 Argonaute 2 (AGO2)。 mitomiR-2392 识别 H 链中的靶序列，并以细胞特异性方式部分抑制多顺反子 mtDNA 转录。对 TSCC 患者肿瘤的回顾性分析揭示了 miR-2392 和调节的线粒体基因表达与化疗敏感性和总体生存率之间的显着相关性。 TCGA RNA 测序在多种类型的癌症中一致验证了靶向线粒体基因的临床相关性。我们的研究首次揭示了mitomiR在mtDNA转录中的作用及其对肿瘤细胞代谢和化疗耐药的分子基础的贡献。
MicroRNAs (miRNA) that translocate from the nucleus to mitochondria are referred to as mitochondrial microRNAs (mitomiR). mitomiR have been shown to modulate the translational activity of the mitochondrial genome, yet their role in mitochondrial DNA(mtDNA) transcription remains to be determined. Here we report that the mitomiR-2392 regulates chemoresistance in tongue squamous cell carcinoma (TSCC) cells by reprogramming metabolism via downregulation of oxidative phosphorylation (OXPHOS) and upregulation of glycolysis. These effects were mediated through partial inhibition of mtDNA transcription by mitomiR-2392 rather than through translational regulation. This repression required specific miRNA-mtDNA base pairing and Argonaute 2 (AGO2). mitomiR-2392 recognized target sequences in the H-strand and partially inhibited polycistronic mtDNA transcription in a cell-specific manner. A retrospective analysis of TSCC patient tumors revealed a significant association of miR-2392 and regulated mitochondrial gene expression with chemosensitivity and overall survival. The clinical relevance of targeted mitochondrial genes was consistently validated by TCGA RNA sequencing in multiple types of cancer. Our study revealed for the first time the role of mitomiR in mtDNA transcription and its contribution to the molecular basis of tumor cell metabolism and chemoresistance.