Guo Junchao, Kleeff Jörg, Zhao Yupei, Li Junsheng, Giese Thomas, Esposito Irene, Büchler Markus W, Korc Murray, Friess Helmut
Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
Int J Mol Med. 2006 May;17(5):761-7.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by multiple alterations in the TGF-beta signaling pathway. Yes-associated protein (YAP65) interacts with Smad7 thereby influencing TGF-beta signaling. In the present study, the expression of YAP65 in PDAC was analyzed in order to elucidate the potential role of this molecule in the pathogenesis of pancreatic cancer. YAP65 mRNA expression levels in human pancreatic tissue samples and cell lines were analyzed by Northern blotting and quantitative RT-PCR. Immunohistochemistry was carried out to localize and quantify YAP65 expression in relation to Smad7 expression and Smad4 mutations. The effects of TGF-beta1 on Smad7 and YAP65 mRNA expression were analyzed by quantitative RT-PCR. Enhanced expression of YAP65 mRNA was identified by Northern blotting and quantitative RT-PCR in PDAC in comparison to the normal pancreas (2.5-fold increase) and to chronic pancreatitis (1.3-fold increase). In the normal pancreas, YAP65 was absent in acinar cells, large ducts and islet cells, but exhibited moderate to strong immunoreactivity in centroacinar cells and ductules. Tubular complexes in CP and CP-like lesions in PDAC also exhibited strong staining. In contrast, weak to moderate YAP65 immunoreactivity was present in the cancer cells. There was no correlation between YAP65 immunostaining and Smad7 staining or Smad4 mutations in the cancer samples. TGF-beta1 strongly induced Smad7 mRNA in Colo-357 and in Panc-1 cells, but only slightly induced YAP65 mRNA in Colo-357 cells. In conclusion, YAP65 is expressed mainly in centroacinar and small ductal cells in the normal pancreas. In PDAC, YAP65 is present in tubular complexes and to a lesser extent in cancer cells. Together with the known function of YAP65 in different growth and differentiation regulating pathways, it is suggested that this gene plays a role in the normal and diseased pancreas.
胰腺导管腺癌（PDAC）的特征是转化生长因子-β（TGF-β）信号通路存在多种改变。Yes相关蛋白（YAP65）与Smad7相互作用，从而影响TGF-β信号传导。在本研究中，分析了YAP65在PDAC中的表达，以阐明该分子在胰腺癌发病机制中的潜在作用。通过Northern印迹法和定量逆转录-聚合酶链反应（RT-PCR）分析了人胰腺组织样本和细胞系中YAP65 mRNA的表达水平。进行免疫组织化学以定位和定量YAP65表达，并与Smad7表达和Smad4突变相关联。通过定量RT-PCR分析TGF-β1对Smad7和YAP65 mRNA表达的影响。与正常胰腺相比（增加2.5倍）以及与慢性胰腺炎相比（增加1.3倍），通过Northern印迹法和定量RT-PCR在PDAC中鉴定出YAP65 mRNA表达增强。在正常胰腺中，腺泡细胞、大导管和胰岛细胞中不存在YAP65，但在中央腺泡细胞和小导管中表现出中度至强免疫反应性。PDAC中CP和CP样病变中的管状复合体也表现出强染色。相反，癌细胞中存在弱至中度的YAP65免疫反应性。癌症样本中YAP65免疫染色与Smad7染色或Smad4突变之间无相关性。TGF-β1在Colo-357和Panc-1细胞中强烈诱导Smad7 mRNA，但在Colo-357细胞中仅轻微诱导YAP65 mRNA。总之，YAP65主要在正常胰腺的中央腺泡和小导管细胞中表达。在PDAC中，YAP65存在于管状复合体中，在癌细胞中的表达程度较低。结合YAP65在不同生长和分化调节途径中的已知功能，提示该基因在正常和患病胰腺中发挥作用。
