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针对 IRF3 作为 YAP 激动剂治疗胃癌。

Targeting IRF3 as a YAP agonist therapy against gastric cancer.

机构信息

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

出版信息

J Exp Med. 2018 Feb 5;215(2):699-718. doi: 10.1084/jem.20171116. Epub 2018 Jan 16.

DOI:10.1084/jem.20171116
PMID:29339449
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5789414/
Abstract

The Hippo pathway plays a vital role in tissue homeostasis and tumorigenesis. The transcription factor IRF3 is essential for innate antiviral immunity. In this study, we discovered IRF3 as an agonist of Yes-associated protein (YAP). The expression of IRF3 is positively correlated with that of YAP and its target genes in gastric cancer; the expression of both IRF3 and YAP is up-regulated and prognosticates patient survival. IRF3 interacts with both YAP and TEAD4 in the nucleus to enhance their interaction, promoting nuclear translocation and activation of YAP. IRF3 and YAP-TEAD4 are associated genome-wide to cobind and coregulate many target genes of the Hippo pathway. Overexpression of active IRF3 increased, but depletion of IRF3 reduced, the occupancy of YAP on the target genes. Knockdown or pharmacological targeting of IRF3 by Amlexanox, a drug used clinically for antiinflammatory treatment, inhibits gastric tumor growth in a YAP-dependent manner. Collectively, our study identifies IRF3 as a positive regulator for YAP, highlighting a new therapeutic target against YAP-driven cancers.

摘要

Hippo 通路在组织稳态和肿瘤发生中起着至关重要的作用。转录因子 IRF3 是先天抗病毒免疫所必需的。在这项研究中，我们发现 IRF3 是 Yes 相关蛋白 (YAP) 的激动剂。IRF3 的表达与胃癌中的 YAP 及其靶基因的表达呈正相关；IRF3 和 YAP 的表达均上调，并预示着患者的生存。IRF3 在核内与 YAP 和 TEAD4 相互作用，增强它们的相互作用，促进 YAP 的核易位和激活。IRF3 和 YAP-TEAD4 与全基因组相关联，共同结合和调控 Hippo 通路的许多靶基因。活性 IRF3 的过表达增加，但 IRF3 的耗竭减少了 YAP 对靶基因的占有率。用 Amlexanox（一种用于抗炎治疗的临床药物）敲低或药理学靶向作用于 IRF3，以 YAP 依赖性方式抑制胃肿瘤生长。总的来说，我们的研究确定了 IRF3 是 YAP 的正调节剂，突出了针对 YAP 驱动的癌症的新治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/6c322ece2212/JEM_20171116_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/9371f5cbf166/JEM_20171116_GA.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/524bed9ef29c/JEM_20171116_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/42389a4b0c75/JEM_20171116_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/1cac97a0b98f/JEM_20171116_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/710302ef8e20/JEM_20171116_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/a68d1429dfeb/JEM_20171116_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/d73660c1dd39/JEM_20171116_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/6c322ece2212/JEM_20171116_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/9371f5cbf166/JEM_20171116_GA.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/524bed9ef29c/JEM_20171116_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/42389a4b0c75/JEM_20171116_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/1cac97a0b98f/JEM_20171116_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/710302ef8e20/JEM_20171116_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/a68d1429dfeb/JEM_20171116_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/d73660c1dd39/JEM_20171116_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a4/5789414/6c322ece2212/JEM_20171116_Fig7.jpg

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