Role of Kallistatin Treatment in Aging and Cancer by Modulating miR-34a and miR-21 Expression.
Role of Kallistatin Treatment in Aging and Cancer by Modulating miR-34a and miR-21 Expression.
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DOI：
10.1155/2017/5025610
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发表时间：
2017
影响因子：
--
通讯作者：
Chao L
中科院分区：
文献类型：
--
作者：
Chao J;Guo Y;Li P;Chao L
Kallistatin是一种内源性蛋白质，通过其两个结构元件调节差异信号传导途径和广泛的生物活性：活性位点和肝素结合结构域。Kallistatin通过其肝素结合位点通过拮抗TNF-α诱导的NADPH氧化酶活性、NF-κB活化和内皮细胞中的炎性基因表达来抑制血管炎症和氧化应激。此外，Kallistatin通过其活性位点抑制microRNA-34 a（miR-34 a）合成并刺激内皮祖细胞中eNOS和SIRT 1的表达，而其肝素结合位点对于阻断TNF-α诱导的miR-21表达和氧化应激至关重要，从而减少细胞衰老。通过下调miR-34 a和miR-21的表达，激肽抑制素治疗减轻了链脲佐菌素诱导的糖尿病小鼠的氧化损伤和主动脉衰老，并延长了应激条件下秀丽隐杆线虫的寿命。同样，通过肝素结合位点，激肽释放酶抑制剂抑制TGF-β诱导的内皮细胞中miR-21的合成和氧化应激，从而抑制内皮-间充质转化，这是一个导致纤维化和癌症的过程。此外，激肽释放酶抑制剂的活性位点对于刺激miR-34 a和p53表达以及抑制miR-21-Akt-Bcl-2信号通路，从而诱导乳腺癌细胞凋亡是必不可少的。这些发现揭示了Kallistatin通过调节miR-34 a和miR-21水平并抑制氧化应激来保护免受衰老，衰老和癌症发展的新机制。
Kallistatin is an endogenous protein that regulates differential signaling pathways and a wide spectrum of biological activities via its two structural elements: an active site and a heparin-binding domain. Kallistatin via its heparin-binding site inhibits vascular inflammation and oxidative stress by antagonizing TNF-α-induced NADPH oxidase activity, NF-κB activation, and inflammatory gene expression in endothelial cells. Moreover, kallistatin via its active site inhibits microRNA-34a (miR-34a) synthesis and stimulates eNOS and SIRT1 expression in endothelial progenitor cells, whereas its heparin-binding site is crucial for blocking TNF-α-induced miR-21 expression and oxidative stress, thus reducing cellular senescence. By downregulating miR-34a and miR-21 expression, kallistatin treatment attenuates oxidative damage and aortic senescence in streptozotocin-induced diabetic mice and extends Caenorhabditis elegans lifespan under stress conditions. Likewise, kallistatin through the heparin-binding site inhibits TGF-β-induced miR-21 synthesis and oxidative stress in endothelial cells, resulting in inhibition of endothelial-mesenchymal transition, a process contributing to fibrosis and cancer. Furthermore, kallistatin's active site is essential for stimulating miR-34a and p53 expression and inhibiting the miR-21-Akt-Bcl-2 signaling pathway, thus inducing apoptosis in breast cancer cells. These findings reveal novel mechanisms of kallistatin in protection against senescence, aging, and cancer development by modulating miR-34a and miR-21 levels and inhibiting oxidative stress.