Zinc-Dependent Regulation of ZEB1 and YAP1 Coactivation Promotes Epithelial-Mesenchymal Transition Plasticity and Metastasis in Pancreatic Cancer.
Zinc-Dependent Regulation of ZEB1 and YAP1 Coactivation Promotes Epithelial-Mesenchymal Transition Plasticity and Metastasis in Pancreatic Cancer.
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DOI：
10.1053/j.gastro.2020.12.077
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发表时间：
2021-04
期刊：
影响因子：
29.4
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
Liu M;Zhang Y;Yang J;Zhan H;Zhou Z;Jiang Y;Shi X;Fan X;Zhang J;Luo W;Fung KA;Xu C;Bronze MS;Houchen CW;Li M
胰腺癌的特点是广泛转移。EMT可塑性通过维持EMT和MET状态之间的转换在肿瘤进展和转移中起关键作用。我们的目的是了解调节胰腺癌转移和EMT可塑性的分子事件。在人胰腺癌细胞、临床标本、自发小鼠模型（KPC和KPCZ）和原位异种移植物以及3D球状体和类器官模型中检查了促癌锌转运蛋白ZIP 4、锌依赖性EMT转录因子ZEB 1、共激活因子YAP 1和整合素α3（ITGA 3）之间的相互作用。通过RNA原位杂交和IHC染色评估ZIP 4、miR-373及其下游靶标之间的相关性。通过ChIP、Co-IP和荧光素酶报告基因检测ZIP 4对ZEB 1、YAP 1、ITGA 3的转录调控。Hippo途径效应子YAP 1是一种有效的转录共激活因子，与ZEB 1形成复合物，通过人胰腺癌细胞和KPC衍生小鼠细胞中的YAP 1/TEAD结合位点激活ITGA 3转录。ZIP 4通过激活miR-373和抑制YAP 1阻遏物LATS 2上调YAP 1表达。此外，ZIP 4的上调通过ZEB 1/YAP 1-ITGA 3信号传导轴促进人胰腺癌细胞、3D球体模型、异种移植模型和自发小鼠模型（KPC和KPCZ）中的EMT可塑性、细胞粘附、球体形成和器官形成。我们证明ZIP 4通过不同的机制激活ZEB 1和YAP 1。ZIP 4-miR-373-LATS 2-ZEB 1/YAP 1-ITGA 3信号轴对胰腺癌转移和EMT可塑性具有显著影响。本研究定义了一种新的ZIP 4-miR-373-LATS 2-ZEB 1/YAP 1-ITGA 3信号通路，其介导胰腺癌转移和EMT可塑性。这些发现对于开发胰腺癌的新的个性化治疗具有高度的转化作用。
Pancreatic cancer is characterized by extensive metastasis. EMT plasticity plays a critical role in tumor progression and metastasis by maintaining the transition between EMT and MET states. Our aim is to understand the molecular events regulating metastasis and EMT plasticity in pancreatic cancer. The interactions between a cancer promoting zinc transporter ZIP4, a zinc dependent EMT transcriptional factor ZEB1, a co-activator YAP1, and integrin α3 (ITGA3) were examined in human pancreatic cancer cells, clinical specimens, spontaneous mouse models (KPC and KPCZ) and orthotopic xenografts, and 3D spheroid and organoid models. Correlations between ZIP4, miR-373, and its downstream targets were assessed by RNA in situ hybridization and IHC staining. The transcriptional regulation of ZEB1, YAP1, ITGA3 by ZIP4 was determined by ChIP, Co-IP and luciferase reporter assays. The Hippo pathway effector YAP1 is a potent transcriptional co-activator and forms a complex with ZEB1 to activate ITGA3 transcription through the YAP1/TEAD binding sites in human pancreatic cancer cells and KPC derived mouse cells. ZIP4 upregulated YAP1 expression via activation of miR-373 and inhibition of the YAP1 repressor LATS2. Furthermore, upregulation of ZIP4 promoted EMT plasticity, cell adhesion, spheroid formation and organogenesis both in human pancreatic cancer cells, 3D spheroid model, xenograft model, and spontaneous mouse models (KPC and KPCZ) through ZEB1/YAP1-ITGA3 signaling axis. We demonstrated that ZIP4 activates ZEB1 and YAP1 through distinct mechanisms. The ZIP4-miR-373-LATS2-ZEB1/YAP1-ITGA3 signaling axis has a significant impact on pancreatic cancer metastasis and EMT plasticity. This study defines a novel ZIP4-miR-373-LATS2-ZEB1/YAP1-ITGA3 signaling pathway that meditates pancreatic cancer metastasis and EMT plasticity. The findings are highly translational to develop new personalized therapy for pancreatic cancer.
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影响因子：
10.5
作者：
Meng Z;Moroishi T;Guan KL
通讯作者：
Guan KL
影响因子：
7.5
作者：
Campbell K
通讯作者：
Campbell K
影响因子：
29.4
作者：
Liu M;Zhang Y;Yang J;Cui X;Zhou Z;Zhan H;Ding K;Tian X;Yang Z;Fung KA;Edil BH;Postier RG;Bronze MS;Fernandez-Zapico ME;Stemmler MP;Brabletz T;Li YP;Houchen CW;Li M
通讯作者：
Li M
DOI：
10.1073/pnas.0709307104
发表时间：
2007-11-20
影响因子：
11.1
作者：
Li, Min;Zhang, Yuqing;Yao, Qizhi
通讯作者：
Yao, Qizhi
影响因子：
16.6
作者：
Nardone G;Oliver-De La Cruz J;Vrbsky J;Martini C;Pribyl J;Skládal P;Pešl M;Caluori G;Pagliari S;Martino F;Maceckova Z;Hajduch M;Sanz-Garcia A;Pugno NM;Stokin GB;Forte G
通讯作者：
Forte G