title: S100P-binding protein, S100PBP, mediates adhesion through regulation of cathepsin Z in pancreatic cancer cells.
abstract: Several S100 proteins are up-regulated in pancreatic ductal adenocarcinoma (PDAC), the most significant being S100P. We previously reported on S100PBP, a binding partner of S100P, that shows no homology to any described protein and whose functions are completely unknown. To determine S100PBP expression across human tissues and organs, immunohistochemistry was performed using both multiorgan- and in-house-constructed pancreatic tissue microarrays. To establish S100PBP functions, cell lines with either stably overexpressed or silenced S100PBP were generated and investigated using Affymetrix gene expression arrays and complementary functional assays. We show that S100PBP is differentially expressed in various healthy and tumor specimens, which is both cancer- and tissue-type dependent. In healthy pancreas, S100PBP is expressed in the nuclear/perinuclear region of both exocrine and endocrine compartments. In early precancerous lesions, S100PBP is translocated to the cytoplasm, whereas in PDAC and metastatic lesions, its expression is significantly diminished. The most pronounced phenotypic change after manipulation of S100PBP expression was seen in adhesion; this was significantly reduced after S100PBP up-regulation and increased after S100PBP silencing. Up-regulation or silencing of S100PBP also led to a concomitant change in the levels of the protease cathepsin Z, the silencing of which significantly reduced PDAC cell adhesion. We further demonstrate that the interaction of cathepsin Z with arginine-glycine-aspartic acid-binding integrins, specifically αvβ5, mediates the changes seen in adhesion of PDAC cells.
authors.affiliation: Center for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Lines
authors.forename: Claude
authors.initials: C
authors.lastname: Chelala
authors.forename: Branko
authors.initials: B
authors.lastname: Dmitrovic
authors.forename: Nilukshi
authors.initials: N
authors.lastname: Wijesuriya
authors.forename: Hemant M
authors.initials: HM
authors.lastname: Kocher
authors.forename: John F
authors.initials: JF
authors.lastname: Marshall
authors.forename: Tatjana
authors.initials: T
authors.lastname: Crnogorac-Jurcevic
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D056663:Cathepsin Z / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D020868:Gene Silencing; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008207:Lymphatic Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D014407:Tumor Cells, Cultured
chemical_list: D002352:Carrier Proteins; D016023:Integrins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C496889:S100PBP protein, human; C534182:CTSZ protein, human; D056663:Cathepsin Z