YAP1 and TAZ Control Pancreatic Cancer Initiation in Mice by Direct Up-regulation of JAK-STAT3 Signaling.
YAP1 and TAZ Control Pancreatic Cancer Initiation in Mice by Direct Up-regulation of JAK-STAT3 Signaling.
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DOI：
10.1053/j.gastro.2016.05.006
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发表时间：
2016-09
期刊：
影响因子：
29.4
通讯作者：
Behrens A
中科院分区：
文献类型：
--
作者：
Gruber R;Panayiotou R;Nye E;Spencer-Dene B;Stamp G;Behrens A
胰腺炎是胰腺导管腺癌（PDAC）最重要的危险因素。胰腺炎易患PDAC，因为它诱导腺泡细胞重编程的过程，称为腺泡-导管化生（ADM）-胰腺上皮内瘤变病变的前体，可进展为PDAC。KRAS的突变在胰腺肿瘤发生的最早阶段被发现，它似乎是癌症进展的守门人。我们研究了KRAS突变如何与胰腺炎合作，以促进小鼠胰腺癌的进展。我们产生了携带Yap 1和Taz的条件等位基因的小鼠，并在成年小鼠胰腺腺泡细胞中使用Cre-lox重组策略（Yap 1fl/fl;Tazfl/fl; Ela 1-CreERT 2）破坏Yap 1和Taz。我们将这些小鼠与LSL-KrasG 12 D小鼠杂交，LSL-KrasG 12 D小鼠在Cre重组后表达组成型活性形式的KRAS。在化学诱导胰腺炎后分析胰腺肿瘤的发生和进展。我们通过免疫组化分析了胰腺炎或PDAC患者的胰腺组织。在正常的，未转化的腺泡细胞在小鼠胰腺组织中的KRAS致癌激活导致胰腺炎诱导的ADM的水平增加。在这个系统中的KRAS的组成型活性形式的表达导致转录调节因子YAP 1和TAZ的激活，它们的功能是胰腺炎诱导的ADM在小鼠中所需的。JAK-STAT 3通路是通过YAP 1和TAZ的KRAS信号传导的下游效应子。YAP 1和TAZ直接介导JAK-STAT 3信号通路中几个基因的转录激活;这可能是表达激活的KRAS的腺泡细胞对炎症敏感的机制。我们确定了致癌KRAS促进ADM的机制，从而产生启动肿瘤进展的细胞。这一过程涉及腺泡细胞中YAP 1和TAZ的激活，它们上调JAK-STAT 3信号传导，以促进小鼠PDAC的发育。
Pancreatitis is the most important risk factor for pancreatic ductal adenocarcinoma (PDAC). Pancreatitis predisposes to PDAC because it induces a process of acinar cell reprogramming known as acinar-to-ductal metaplasia (ADM)—a precursor of pancreatic intraepithelial neoplasia lesions that can progress to PDAC. Mutations in KRAS are found at the earliest stages of pancreatic tumorigenesis, and it appears to be a gatekeeper to cancer progression. We investigated how mutations in KRAS cooperate with pancreatitis to promote pancreatic cancer progression in mice. We generated mice carrying conditional alleles of Yap1 and Taz and disrupted Yap1 and Taz using a Cre-lox recombination strategy in adult mouse pancreatic acinar cells (Yap1fl/fl;Tazfl/fl;Ela1-CreERT2). We crossed these mice with LSL-KrasG12D mice, which express a constitutively active form of KRAS after Cre recombination. Pancreatic tumor initiation and progression were analyzed after chemically induced pancreatitis. We analyzed pancreatic tissues from patients with pancreatitis or PDAC by immunohistochemistry. Oncogenic activation of KRAS in normal, untransformed acinar cells in the pancreatic tissues of mice resulted in increased levels of pancreatitis-induced ADM. Expression of the constitutive active form of KRAS in this system led to activation of the transcriptional regulators YAP1 and TAZ; their function was required for pancreatitis-induced ADM in mice. The JAK–STAT3 pathway was a downstream effector of KRAS signaling via YAP1 and TAZ. YAP1 and TAZ directly mediated transcriptional activation of several genes in the JAK–STAT3 signaling pathway; this could be a mechanism by which acinar cells that express activated KRAS become susceptible to inflammation. We identified a mechanism by which oncogenic KRAS facilitates ADM and thereby generates the cells that initiate neoplastic progression. This process involves activation of YAP1 and TAZ in acinar cells, which up-regulate JAK–STAT3 signaling to promote development of PDAC in mice.
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影响因子：
8.8
作者：
Eser, S.;Schnieke, A.;Schneider, G.;Saur, D.
通讯作者：
Saur, D.
影响因子：
82.9
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影响因子：
21.3
作者：
Gruber, Ralph;Zhou, Zhongwei;Wang, Zhao-Qi
通讯作者：
Wang, Zhao-Qi
影响因子：
64.5
作者：
Kapoor A;Yao W;Ying H;Hua S;Liewen A;Wang Q;Zhong Y;Wu CJ;Sadanandam A;Hu B;Chang Q;Chu GC;Al-Khalil R;Jiang S;Xia H;Fletcher-Sananikone E;Lim C;Horwitz GI;Viale A;Pettazzoni P;Sanchez N;Wang H;Protopopov A;Zhang J;Heffernan T;Johnson RL;Chin L;Wang YA;Draetta G;DePinho RA
通讯作者：
DePinho RA
影响因子：
64.8
作者：
Biankin, Andrew V.;Waddell, Nicola;Kassahn, Karin S.;Gingras, Marie-Claude;Muthuswamy, Lakshmi B.;Johns, Amber L.;Miller, David K.;Wilson, Peter J.;Patch, Ann-Marie;Wu, Jianmin;Chang, David K.;Cowley, Mark J.;Gardiner, Brooke B.;Song, Sarah;Harliwong, Ivon;Idrisoglu, Senel;Nourse, Craig;Nourbakhsh, Ehsan;Manning, Suzanne;Wani, Shivangi;Gongora, Milena;Pajic, Marina;Scarlett, Christopher J.;Gill, Anthony J.;Pinho, Andreia V.;Rooman, Ilse;Anderson, Matthew;Holmes, Oliver;Leonard, Conrad;Taylor, Darrin;Wood, Scott;Xu, Qinying;Nones, Katia;Fink, J. Lynn;Christ, Angelika;Bruxner, Tim;Cloonan, Nicole;Kolle, Gabriel;Newell, Felicity;Pinese, Mark;Mead, R. Scott;Humphris, Jeremy L.;Kaplan, Warren;Jones, Marc D.;Colvin, Emily K.;Nagrial, Adnan M.;Humphrey, Emily S.;Chou, Angela;Chin, Venessa T.;Chantrill, Lorraine A.;Mawson, Amanda;Samra, Jaswinder S.;Kench, James G.;Lovell, Jessica A.;Daly, Roger J.;Merrett, Neil D.;Toon, Christopher;Epari, Krishna;Nguyen, Nam Q.;Barbour, Andrew;Zeps, Nikolajs;Kakkar, Nipun;Zhao, Fengmei;Wu, Yuan Qing;Wang, Min;Muzny, Donna M.;Fisher, William E.;Brunicardi, F. Charles;Hodges, Sally E.;Reid, Jeffrey G.;Drummond, Jennifer;Chang, Kyle;Han, Yi;Lewis, Lora R.;Dinh, Huyen;Buhay, Christian J.;Beck, Timothy;Timms, Lee;Sam, Michelle;Begley, Kimberly;Brown, Andrew;Pai, Deepa;Panchal, Ami;Buchner, Nicholas;De Borja, Richard;Denroche, Robert E.;Yung, Christina K.;Serra, Stefano;Onetto, Nicole;Mukhopadhyay, Debabrata;Tsao, Ming-Sound;Shaw, Patricia A.;Petersen, Gloria M.;Gallinger, Steven;Hruban, Ralph H.;Maitra, Anirban;Iacobuzio-Donahue, Christine A.;Schulick, Richard D.;Wolfgang, Christopher L.;Morgan, Richard A.;Lawlor, Rita T.;Capelli, Paola;Corbo, Vincenzo;Scardoni, Maria;Tortora, Giampaolo;Tempero, Margaret A.;Mann, Karen M.;Jenkins, Nancy A.;Perez-Mancera, Pedro A.;Adams, David J.;Largaespada, David A.;Wessels, Lodewyk F. A.;Rust, Alistair G.;Stein, Lincoln D.;Tuveson, David A.;Copeland, Neal G.;Musgrove, Elizabeth A.;Scarpa, Aldo;Eshleman, James R.;Hudson, Thomas J.;Sutherland, Robert L.;Wheeler, David A.;Pearson, John V.;McPherson, John D.;Gibbs, Richard A.;Grimmond, Sean M.
通讯作者：
Grimmond, Sean M.