Opposing activities of oncogenic MIR17HG and tumor suppressive MIR100HG clusters and their gene targets regulate replicative senescence in human adult stem cells.
Opposing activities of oncogenic MIR17HG and tumor suppressive MIR100HG clusters and their gene targets regulate replicative senescence in human adult stem cells.
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DOI：
10.1038/s41514-017-0006-y
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发表时间：
2017
影响因子：
5
通讯作者：
Lunyak VV
中科院分区：
文献类型：
--
作者：
Lopez MF;Niu P;Wang L;Vogelsang M;Gaur M;Krastins B;Zhao Y;Smagul A;Nussupbekova A;Akanov AA;Jordan IK;Lunyak VV
越来越多的证据表明，许多衰老疾病，包括与强劲变化和脂肪沉积相关的疾病，可能是由于被称为细胞衰老的过程而导致的常驻成人干细胞衰竭所致。了解microRNA通路如何调节细胞衰老对于开发新的诊断和治疗策略以对抗这些病理是至关重要的。在这里，利用整合的转录和半定量蛋白质组学分析，我们提供了一个系统水平的观点，通过成熟的microRNAs(称为衰老相关microRNAs)对人类脂肪干细胞衰老的调控，这些microRNAs是由致癌的MIR17HG和肿瘤抑制的MIR100HG簇的生物发生产生的。我们证明了这些成熟的衰老相关microRNAs在人类脂肪干细胞体外复制衰老过程中的功能意义，并定义了一组能够诱导、调节、最重要的是平衡致癌和衰老事件之间密切联系的衰老相关microRNA基因靶点。越来越多的证据表明，细胞衰老和人类成年干细胞在衰老时的功能之间存在联系。衰老通常被认为是防止致癌转化的内在程序。然而，由Aelan细胞技术公司领导的合作研究表明，复制性衰老可能比之前预期的更有活力。对人类成体干细胞的综合基因组和蛋白质组分析表明，衰老相关miRNAs(SA-miRNA)在功能上是建立衰老所必需的，在促进和抑制衰老时的癌症事件之间提供了复杂的平衡。人们普遍认为，癌症的发生是细胞内稳态失衡的结果。这些新的结果阐明了这些SA-miRNA作为基因网络功能拮抗调节因子的基础作用，未来对其的探索可以帮助我们理解年龄相关疾病和癌症的病因。
Growing evidence suggests that many diseases of aging, including diseases associated with robust changes and adipose deports, may be caused by resident adult stem cell exhaustion due to the process called cellular senescence. Understanding how microRNA pathways can regulate cellular senescence is crucial for the development of novel diagnostic and therapeutic strategies to combat these pathologies. Herein, using integrated transcriptomic and semi-quantitative proteomic analysis, we provide a system level view of the regulation of human adipose-derived stem cell senescence by a subset of mature microRNAs (termed senescence-associated-microRNAs) produced by biogenesis of oncogenic MIR17HG and tumor-suppressive MIR100HG clusters. We demonstrate functional significance of these mature senescence-associated-microRNAs in the process of replicative senescence of human adipose-derived stem cells ex-vivo and define a set of senescence-associated-microRNA gene targets that are able to elicit, modulate and, most importantly, balance intimate connections between oncogenic and senescent events. Mounting evidence suggests a link between cellular senescence and human adult stem cell function upon aging. Senescence is often viewed as an intrinsic program to prevent oncogenic transformation. However, the collaborative research lead by Aelan Cell Technologies suggests that replicative senescence might be more dynamic than previously anticipated. Integrated genomic and proteomic analyses of human adult stem cells revealed that subset of senescence-associated miRNAs (SA-miRNA) functionally required for establishing senescence, act to provide an intricate balance between driving and restraining cancerous events upon senescence. It is commonly believed that cancer arises as a consequence of an imbalance in cellular homeostasis. These new results shed light on the fundamental role of these SA-miRNA as functionally antagonistic regulators of gene networks, future exploration of which can help us understand the etiology underlying age-related disease and cancer.