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SIRT2的下调通过自噬成分外泌体的释放减少了ASS诱导的非小细胞肺癌细胞凋亡。

Down Regulation of SIRT2 Reduced ASS Induced NSCLC Apoptosis Through the Release of Autophagy Components Exosomes.

作者信息

Wang Lei, Xu Pei, Xie Xiao, Hu Fengqing, Jiang Lianyong, Hu Rui, Ding Fangbao, Xiao Haibo, Zhang Huijun

机构信息

Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Department of Cardiothoracic Surgery, Huashan Hospital of Fudan University, Shanghai, China.

出版信息

Front Cell Dev Biol. 2020 Dec 3;8:601953. doi: 10.3389/fcell.2020.601953. eCollection 2020.

DOI:10.3389/fcell.2020.601953
PMID:33344455
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7744594/
Abstract

Metastasis of cancer is the main cause of death in many types of cancer. Acute shear stress (ASS) is an important part of tumor micro-environment, it plays a crucial role in tumor invasion and spread. However, less is known about the role of ASS in tumorigenesis and metastasis of NSCLC. In this study, NSCLC cells were exposed to ASS (10 dyn/cm) to explore the effect of ASS in regulation of autophagy and exosome mediated cell survival. Finally, the influence of SIRT2 on NSCLC cell metastasis was verified . Our data demonstrates that ASS promotes exosome and autophagy components releasing in a time dependent manner, inhibition of exosome release exacerbates ASS induced NSCLC cell apoptosis. Furthermore, we identified that this function was regulated by sirtuin 2 (SIRT2). And, RNA immunoprecipitation (RIP) assay suggested SIRT2 directly bound to the 3'UTR of transcription factor EB (TFEB) and facilitated its mRNA stability. TFEB is a key transcription factor involved in the regulation of many lysosome related genes and plays a critical role in the fusion of autophagosome and lysosome. Altogether, this data revealed that SIRT2 is a mechanical sensitive protein, and it regulates ASS induced cell apoptosis by modulating the release of exosomes and autophagy components, which provides a promising strategy for the treatment of NSCLCs.

摘要

癌症转移是多种癌症死亡的主要原因。急性剪切应力（ASS）是肿瘤微环境的重要组成部分，在肿瘤侵袭和扩散中起关键作用。然而，关于ASS在非小细胞肺癌（NSCLC）发生和转移中的作用知之甚少。在本研究中，将NSCLC细胞暴露于ASS（10达因/平方厘米）以探讨ASS在调节自噬和外泌体介导的细胞存活中的作用。最后，验证了SIRT2对NSCLC细胞转移的影响。我们的数据表明，ASS以时间依赖性方式促进外泌体和自噬成分的释放，抑制外泌体释放会加剧ASS诱导的NSCLC细胞凋亡。此外，我们确定该功能受沉默调节蛋白2（SIRT2）调控。并且，RNA免疫沉淀（RIP）分析表明SIRT2直接与转录因子EB（TFEB）的3'非翻译区结合并促进其mRNA稳定性。TFEB是参与调控许多溶酶体相关基因的关键转录因子，在自噬体与溶酶体融合中起关键作用。总之，这些数据表明SIRT2是一种机械敏感蛋白，它通过调节外泌体和自噬成分的释放来调节ASS诱导的细胞凋亡，这为NSCLCs的治疗提供了一种有前景的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/c045f422d13e/fcell-08-601953-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/5059ae981421/fcell-08-601953-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/9de6179c2012/fcell-08-601953-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/ce60f41604e0/fcell-08-601953-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/678138aa27d8/fcell-08-601953-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/ad513793455a/fcell-08-601953-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/6a3ce1f92990/fcell-08-601953-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/c045f422d13e/fcell-08-601953-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/5059ae981421/fcell-08-601953-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/9de6179c2012/fcell-08-601953-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/ce60f41604e0/fcell-08-601953-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/26725dead29b/fcell-08-601953-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/678138aa27d8/fcell-08-601953-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/2f3567f90e04/fcell-08-601953-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/ad513793455a/fcell-08-601953-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/6a3ce1f92990/fcell-08-601953-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664c/7744594/c045f422d13e/fcell-08-601953-g009.jpg

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