title: Yes-associated protein (YAP65) in relation to Smad7 expression in human pancreatic ductal adenocarcinoma.
abstract: 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.
authors.affiliation: Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Junchao
authors.initials: J
authors.lastname: Guo
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
authors.forename: Yupei
authors.initials: Y
authors.lastname: Zhao
authors.forename: Junsheng
authors.initials: J
authors.lastname: Li
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Murray
authors.initials: M
authors.lastname: Korc
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015152:Blotting, Northern; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics; D051906:Smad7 Protein / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D012333:RNA, Messenger; C497796:SMAD4 protein, human; C497806:SMAD7 protein, human; D051901:Smad4 Protein; D051906:Smad7 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human