title: Inflammation and pancreatic cancer: molecular and functional interactions between S100A8, S100A9, NT-S100A8 and TGFβ1.
abstract: BACKGROUND
  In order to gain further insight on the crosstalk between pancreatic cancer (PDAC) and stromal cells, we investigated interactions occurring between TGFβ1 and the inflammatory proteins S100A8, S100A9 and NT-S100A8, a PDAC-associated S100A8 derived peptide, in cell signaling, intracellular calcium (Cai2+) and epithelial to mesenchymal transition (EMT). NF-κB, Akt and mTOR pathways, Cai2+ and EMT were studied in well (Capan1 and BxPC3) and poorly differentiated (Panc1 and MiaPaCa2) cell lines.
  
  
  RESULTS
  NT-S100A8, one of the low molecular weight N-terminal peptides from S100A8 to be released by PDAC-derived proteases, shared many effects on NF-κB, Akt and mTOR signaling with S100A8, but mainly with TGFβ1. The chief effects of S100A8, S100A9 and NT-S100A8 were to inhibit NF-κB and stimulate mTOR; the molecules inhibited Akt in Smad4-expressing, while stimulated Akt in Smad4 negative cells. By restoring Smad4 expression in BxPC3 and silencing it in MiaPaCa2, S100A8 and NT-S100A8 were shown to inhibit NF-κB and Akt in the presence of an intact TGFβ1 canonical signaling pathway. TGFβ1 counteracted S100A8, S100A9 and NT-S100A8 effects in Smad4 expressing, not in Smad4 negative cells, while it synergized with NT-S100A8 in altering Cai2+ and stimulating PDAC cell growth. The effects of TGFβ1 on both EMT (increased Twist and decreased N-Cadherin expression) and Cai2+ were antagonized by S100A9, which formed heterodimers with TGFβ1 (MALDI-TOF/MS and co-immuno-precipitation).
  
  
  CONCLUSIONS
  The effects of S100A8 and S100A9 on PDAC cell signaling appear to be cell-type and context dependent. NT-S100A8 mimics the effects of TGFβ1 on cell signaling, and the formation of complexes between TGFβ1 with S100A9 appears to be the molecular mechanism underlying the reciprocal antagonism of these molecules on cell signaling, Cai2+ and EMT.
authors.affiliation: Department of Laboratory Medicine, University-Hospital of Padova, Via Giustiniani 2, 35128 Padova, Italy. daniela.basso@sanita.padova.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Basso
authors.forename: Dania
authors.initials: D
authors.lastname: Bozzato
authors.forename: Andrea
authors.initials: A
authors.lastname: Padoan
authors.forename: Stefania
authors.initials: S
authors.lastname: Moz
authors.forename: Carlo-Federico
authors.initials: CF
authors.lastname: Zambon
authors.forename: Paola
authors.initials: P
authors.lastname: Fogar
authors.forename: Eliana
authors.initials: E
authors.lastname: Greco
authors.forename: Michele
authors.initials: M
authors.lastname: Scorzeto
authors.forename: Francesca
authors.initials: F
authors.lastname: Simonato
authors.forename: Filippo
authors.initials: F
authors.lastname: Navaglia
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.forename: Michela
authors.initials: M
authors.lastname: Pelloso
authors.forename: Sirio
authors.initials: S
authors.lastname: Dupont
authors.forename: Sergio
authors.initials: S
authors.lastname: Pedrazzoli
authors.forename: Ambrogio
authors.initials: A
authors.lastname: Fassina
authors.forename: Mario
authors.initials: M
authors.lastname: Plebani
mesh_terms: D020013:Calcium Signaling; D040501:Calgranulin A / Q000378:metabolism*; D040502:Calgranulin B / Q000378:metabolism*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D016328:NF-kappa B; D010446:Peptide Fragments; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt