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首页> 外文期刊>Molecular and Cellular Biology >MicroRNA 211 Functions as a Metabolic Switch in Human Melanoma Cells
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MicroRNA 211 Functions as a Metabolic Switch in Human Melanoma Cells

机译：MicroRNA 211在人类黑素瘤细胞中充当代谢开关。

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MicroRNA 211 (miR-211) negatively regulates genes that drive invasion of metastatic melanoma. Compared to normal human melanocytes, miR-211 expression is significantly reduced or absent in nonpigmented melanoma cells and lost during human melanoma progression. To investigate the molecular mechanism of its tumor suppressor function, miR-211 was ectopically expressed in nonpigmented melanoma cells. Ectopic expression of miR-211 reduced hypoxia-inducible factor 1α (HIF-1α) protein levels and decreased cell growth during hypoxia. HIF-1α protein loss was correlated with the downregulation of a miR-211 target gene, pyruvate dehydrogenase kinase 4 (PDK4). We present evidence that resumption of miR-211-mediated downregulation of PDK4 in melanoma cells causes inhibition of invasion by nonpigmented melanomas via HIF-1α protein destabilization. Thus, the tumor suppressor miR-211 acts as a metabolic switch, and its loss is expected to promote cancer hallmarks in human melanomas. Melanoma, one of the deadliest forms of skin cancer, kills nearly 10,000 people in the United States per year. We had previously shown that a small noncoding RNA, termed miR-211, suppresses invasion and the growth of aggressive melanoma cells. The results presented here support the hypothesis that miR-211 loss in melanoma cells causes abnormal regulation of energy metabolism, which in turn allows cancer cells to survive under low oxygen concentrations—a condition that generally kills normal cells. These findings highlight a novel mechanism of melanoma formation: miR-211 is a molecular switch that is turned off in melanoma cells, raising the hope that in the future we might be able to turn the switch back on, thus providing a better treatment option for melanoma.
机译：MicroRNA 211（miR-211）负调控驱动转移性黑色素瘤侵袭的基因。与正常人黑素细胞相比，未染色的黑素瘤细胞中miR-211表达显着降低或缺失，并且在人类黑素瘤进展过程中丢失。为了研究其抑癌功能的分子机制，miR-211在非色素黑色素瘤细胞中异位表达。 miR-211的异位表达降低了低氧诱导因子1α（HIF-1α）蛋白的水平，并降低了低氧过程中的细胞生长。 HIF-1α蛋白的丢失与miR-211靶基因丙酮酸脱氢酶激酶4（ PDK4 ）的下调有关。我们提供的证据表明，恢复黑色素瘤细胞中miR-211介导的 PDK4 的下调会通过HIF-1α蛋白去稳定作用抑制非色素性黑色素瘤的侵袭。因此，肿瘤抑制物miR-211充当代谢开关，并且预期其丧失将促进人黑素瘤的癌症标志。黑色素瘤是最致命的皮肤癌之一，每年在美国杀死近10,000人。先前我们已经表明，称为miR-211的小的非编码RNA会抑制侵袭性黑色素瘤细胞的生长。此处提出的结果支持以下假设：黑色素瘤细胞中miR-211的丢失会导致能量代谢的异常调节，这反过来又使癌细胞能够在低氧浓度下存活（这种条件通常会杀死正常细胞）。这些发现凸显了黑色素瘤形成的新机制：miR-211是一种在黑色素瘤细胞中关闭的分子开关，人们希望在将来我们能够重新打开该开关，从而提供更好的治疗选择黑色素瘤。

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