title: Quantitative proteomic profiling identifies DPYSL3 as pancreatic ductal adenocarcinoma-associated molecule that regulates cell adhesion and migration by stabilization of focal adhesion complex.
abstract: Elucidation of how pancreatic cancer cells give rise to distant metastasis is urgently needed in order to provide not only a better understanding of the underlying molecular mechanisms, but also to identify novel targets for greatly improved molecular diagnosis and therapeutic intervention. We employed combined proteomic technologies including mass spectrometry and isobaric tags for relative and absolute quantification peptide tagging to analyze protein profiles of surgically resected human pancreatic ductal adenocarcinoma tissues. We identified a protein, dihydropyrimidinase-like 3, as highly expressed in human pancreatic ductal adenocarcinoma tissues as well as pancreatic cancer cell lines. Characterization of the roles of dihydropyrimidinase-like 3 in relation to cancer cell adhesion and migration in vitro, and metastasis in vivo was performed using a series of functional analyses, including those employing multiple reaction monitoring proteomic analysis. Furthermore, dihydropyrimidinase-like 3 was found to interact with Ezrin, which has important roles in cell adhesion, motility, and invasion, while that interaction promoted stabilization of an adhesion complex consisting of Ezrin, c-Src, focal adhesion kinase, and Talin1. We also found that exogenous expression of dihydropyrimidinase-like 3 induced activating phosphorylation of Ezrin and c-Src, leading to up-regulation of the signaling pathway. Taken together, the present results indicate successful application of combined proteomic approaches to identify a novel key player, dihydropyrimidinase-like 3, in pancreatic ductal adenocarcinoma tumorigenesis, which may serve as an important biomarker and/or drug target to improve therapeutic strategies.
authors: Division of Molecular Carcinogenesis, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan ; Division of Surgical Oncology, Nagoya University Hospital, Nagoya, Aichi, Japan.
authors: Takeo
authors: T
authors: Kawahara
authors: Naoe
authors: N
authors: Hotta
authors: Yukiko
authors: Y
authors: Ozawa
authors: Seiichi
authors: S
authors: Kato
authors: Keiko
authors: K
authors: Kano
authors: Yukihiro
authors: Y
authors: Yokoyama
authors: Masato
authors: M
authors: Nagino
authors: Takashi
authors: T
authors: Takahashi
authors: Kiyoshi
authors: K
authors: Yanagisawa
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000473:pathology*; D040901:Proteomics; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D009124:Muscle Proteins; D000099149:Ezrin; C102926:DPYSL3 protein, human