Previously we reported that the microRNA miR-210 is aberrantly upregulated in clear cell renal cell carcinoma (ccRCC) via deregulation of the VHL-HIF pathway. In the present study, to investigate the biological impact of miR-210 in ccRCC tumorigenesis, we developed a transgenic mouse line expressing miR-210 in proximal tubule cells under control of the mouse SGLT2/Slc5a2 promoter. Light microscopy revealed desquamation of the tubule cells and regeneration of the proximal tubule, suggesting that miR-210 expression led to damage of the proximal tubule cells. Electron microscopy revealed alterations to the mitochondria in proximal tubule cells, with marked reduction of the mitochondrial inner membrane, which is the main site of ATP production via oxidative phosphorylation (OxPhos). An additional in vitro study revealed that this loss of the inner membrane was associated with downregulation of Iscu and Ndufa4, the target genes of miR-210, suggesting that the miR-210-ISCU/NDUFA4 axis may affect mitochondrial energy metabolism. Furthermore, metabolome analysis revealed activation of anaerobic glycolysis in miR-210-transfected cells, and consistent with this the secretion of lactate, the final metabolite of anaerobic glycolysis, was significantly increased. Lactate concentration was higher in the kidney cortex of transgenic mice relative to wild-type mice, although the difference was not significant (p = 0.070). On the basis of these findings, we propose that miR-210 may induce a shift of energy metabolism from OxPhos to glycolysis by acting on the mitochondrial inner membrane. In addition to activation of glycolysis, we observed activation of the pentose phosphate pathway (PPP) and an increase in the total amount of amino acids in miR-210-transfected cells. This may help cells synthesize nucleotides and proteins for building new cells. These results suggest that miR-210 may be involved in the metabolic changes in the early stage of ccRCC development, helping the cancer cells to acquire growth and survival advantages. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

中文翻译：

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在近端肾小管细胞中表达miR-210的转基因小鼠显示线粒体改变：miR-210与能量代谢改变的可能关联。

之前我们曾报道过，通过清除VHL-HIF通路，在透明细胞肾细胞癌（ccRCC）中microRNA miR-210异常上调。在本研究中，为了研究miR-210在ccRCC肿瘤发生中的生物学影响，我们开发了在小鼠SGLT2 / Slc5a2启动子控制下在近端小管细胞中表达miR-210的转基因小鼠品系。光学显微镜显示小管细胞脱皮和近端小管的再生，表明miR-210表达导致近端小管细胞的损伤。电镜观察发现近端肾小管细胞线粒体发生改变，线粒体内膜明显减少，这是通过氧化磷酸化（OxPhos）产生ATP的主要部位。另一项体外研究表明，内膜的这种丧失与miR-210的靶基因Iscu和Ndufa4的下调有关，这表明miR-210-ISCU / NDUFA4轴可能影响线粒体能量代谢。此外，代谢组学分析显示，miR-210转染的细胞中厌氧糖酵解的激活，与此相一致的是，厌氧糖酵解的最终代谢产物乳酸的分泌显着增加。相对于野生型小鼠，转基因小鼠肾皮质中的乳酸浓度更高，尽管差异不显着（p = 0.070）。根据这些发现，我们提出miR-210可能通过作用于线粒体内膜，从而诱导能量代谢从OxPhos转变为糖酵解。除了激活糖酵解外，我们观察到了戊糖磷酸途径（PPP）的激活和miR-210转染的细胞中氨基酸总量的增加。这可能有助于细胞合成核苷酸和蛋白质以构建新细胞。这些结果表明，miR-210可能参与ccRCC发育的早期代谢变化，从而帮助癌细胞获得生长和生存优势。©2020英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版 帮助癌细胞获得生长和生存优势。©2020英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版 帮助癌细胞获得生长和生存优势。©2020英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版