Short interfering RNA against STAT1 attenuates cisplatin-induced ototoxicity in the rat by suppressing inflammation.
Short interfering RNA against STAT1 attenuates cisplatin-induced ototoxicity in the rat by suppressing inflammation.
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短暂干扰RNA对STAT1的干扰可通过抑制炎症来减弱顺铂诱导的大鼠耳毒性。
DOI：
10.1038/cddis.2011.63
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发表时间：
2011-07-21
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
顺铂广泛用于治疗各种实体肿瘤。然而，该药产生剂量限制性耳毒性和肾毒性，显著降低癌症患者的生活质量。虽然利尿可以减轻肾毒性，但目前还没有批准的治疗听力损失的方法。既往研究表明，ROS和炎症是顺铂所致听力损失的主要原因。在这项研究中，我们发现ROS通过激活信号换能器和转录激活因子-1 （STAT1）来触发耳蜗的炎症过程。STAT1的激活依赖于NOX3 NADPH氧化酶产生的ROS， siRNA敲低NOX3 NADPH氧化酶可降低STAT1的激活。此外，STAT1 siRNA可以抑制p53的激活，减少细胞凋亡，减少ohc损伤，并保护大鼠的听力。STAT1 siRNA减弱炎症介质的增加，如TNF-α，抑制其保护细胞免受顺铂介导的凋亡。最后，我们发现，经鼓室给药依那西普（一种TNF-α拮抗剂）可以防止OHC损伤和顺铂引起的听力损失。这些研究提示，通过抑制耳蜗stat1依赖通路来控制炎症可作为治疗顺铂耳毒性和改善癌症患者整体生活质量的有效途径。
Cisplatin is widely used for treating various solid tumors. However, this drug produces dose-limiting ototoxicity and nephrotoxicity, which significantly reduce the quality of life of cancer patients. While nephrotoxicity could be alleviated by diuresis, there is currently no approved treatment for hearing loss. Previous studies show that the ROS and inflammation are major contributors to cisplatin-induced hearing loss. In this study, we show that ROS trigger the inflammatory process in the cochlea by activating signal transducer and activator of transcription-1 (STAT1). Activation of STAT1 activation was dependent on ROS generation through NOX3 NADPH oxidase, knockdown of which by siRNA reduced STAT1 activation. Moreover, STAT1 siRNA protected against activation of p53, reduced apoptosis, reduced damage to OHCs and preserved hearing in rats. STAT1 siRNA attenuated the increase in inflammatory mediators, such as TNF-α, inhibition of which protected cells from cisplatin-mediated apoptosis. Finally, we showed that trans-tympanic administration of etanercept, a TNF-α antagonist, protected against OHC damage and cisplatin-induced hearing loss. These studies suggest that controlling inflammation by inhibition of STAT1-dependent pathways in the cochlea could serve as an effective approach to treat cisplatin ototoxicity and improve the overall quality of life for cancer patients.
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DOI：
10.1620/tjem.219.177
发表时间：
2009-11
期刊：
The Tohoku journal of experimental medicine
影响因子：
--
作者：
Rybak LP;Mukherjea D;Jajoo S;Ramkumar V
通讯作者：
Ramkumar V
影响因子：
2.2
作者：
Hoshino, Tomofumi;Tabuchi, Keiji;Hara, Akira
通讯作者：
Hara, Akira
影响因子：
8
作者：
Porta, C;Hadj-Slimane, R;Chelbi-Alix, MK
通讯作者：
Chelbi-Alix, MK
DOI：
10.1007/s10162-007-0084-9
发表时间：
2007-09-01
影响因子：
2.4
作者：
So, Hongseob;Kim, Hyungjin;Park, Raekil
通讯作者：
Park, Raekil
影响因子：
15.9
作者：
Ramesh, G;Reeves, WB
通讯作者：
Reeves, WB