Wang Lidong, Yang Huibin, Abel Ethan V, Ney Gina M, Palmbos Phillip L, Bednar Filip, Zhang Yaqing, Leflein Jacob, Waghray Meghna, Owens Scott, Wilkinson John E, Prasad Jayendra, Ljungman Mats, Rhim Andrew D, Pasca di Magliano Marina, Simeone Diane M
Department of Surgery, Translational Oncology Program.
Translational Oncology Program, Department of Pediatrics.
Genes Dev. 2015 Jan 15;29(2):171-83. doi: 10.1101/gad.253591.114.
The initiation of pancreatic ductal adenocarcinoma (PDA) is linked to activating mutations in KRAS. However, in PDA mouse models, expression of oncogenic mutant KRAS during development gives rise to tumors only after a prolonged latency or following induction of pancreatitis. Here we describe a novel mouse model expressing ataxia telangiectasia group D complementing gene (ATDC, also known as TRIM29 [tripartite motif 29]) that, in the presence of oncogenic KRAS, accelerates pancreatic intraepithelial neoplasia (PanIN) formation and the development of invasive and metastatic cancers. We found that ATDC up-regulates CD44 in mouse and human PanIN lesions via activation of β-catenin signaling, leading to the induction of an epithelial-to-mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. We show that ATDC is up-regulated by oncogenic Kras in a subset of PanIN cells that are capable of invading the surrounding stroma. These results delineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT.
胰腺导管腺癌（PDA）的起始与KRAS基因的激活突变有关。然而，在PDA小鼠模型中，发育过程中致癌性突变KRAS的表达仅在长时间潜伏期后或诱发胰腺炎后才会引发肿瘤。在此，我们描述了一种新型小鼠模型，该模型表达共济失调毛细血管扩张症D组互补基因（ATDC，也称为TRIM29 [三联基序29]），在存在致癌性KRAS的情况下，它会加速胰腺上皮内瘤变（PanIN）的形成以及侵袭性和转移性癌症的发展。我们发现，ATDC通过激活β-连环蛋白信号上调小鼠和人类PanIN病变中的CD44，导致诱导以Zeb1和Snail1表达为特征的上皮-间质转化（EMT）表型。我们表明，在能够侵入周围基质的一部分PanIN细胞中，致癌性Kras会上调ATDC。这些结果描绘了胰腺肿瘤发生过程中EMT的一条新分子途径，表明ATDC是EMT的近端调节因子。
