Inflammation and pancreatic cancer: molecular and functional interactions between S100A8, S100A9, NT-S100A8 and TGFβ1

Abstract

BackgroundIn 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.ResultsNT-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).ConclusionsThe 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.

Retracted: S100A9 gene silencing inhibits the release of pro‐inflammatory cytokines by blocking the IL‐17 signalling pathway in mice with acute pancreatitis

“…When combined with S100A8, S100A9 constitutes the heterodimeric protein calprotectin (S100A8/9), which is expressed in nearly all cells, tissues and fluids in the human body . A recent study explored the relationship between pancreatic cancer, S100A9/A8 and transforming growth factor beta 1 (TGFβ1) concluded that the overexpression of S100A9/A8 by infiltrating inflammatory cells and the expressions is related to TGFβ1 in pancreatic ductal adenocarcinoma (PDAC) . Interleukin‐17 (IL‐17), a pro‐inflammatory cytokine mainly produced by T‐helper 17 (Th 17) cells, has been reported to play a crucial role in the development of an effective immune response .…”

Serum amyloid A1 in combination with integrin αVβ3 increases glioblastoma cells mobility and progression

“…Serum biomarkers, S100A8, S100A9, and CXCL4, were identified from GBM patients' serum by using surface‐enhanced laser desorption/ionization time‐of‐flight and liquid chromatography–MS/MS technologies (Popescu et al ., ). Their functions are correlated with acute inflammatory reactions to cancer cells (Basso et al ., ; Gebhardt et al ., ) and disease‐related cystic fibrosis (van Bon et al ., ; Schwartzkopff et al ., ). We applied a similar proteomic methodology and found that the level of the SAA1 protein in the plasma of patients with GBM was higher than that in the plasma of healthy people; this was confirmed through protein blot analysis conducted on different cohorts.…”

SMAD4 loss enables EGF, TGFβ1 and S100A8/A9 induced activation of critical pathways to invasion in human pancreatic adenocarcinoma cells

“…These findings appear in disagreement with those of Levy and Hill [42], who demonstrated that SMAD4 silencing completely abolished TGFβ1 induced migration and this discrepancy might depend on differences between the cellular models and TGFβ1 dosages. We used low amounts of TGFβ1 (0.02 ng/mL) because they were comparable to those used by Yasutome et al [49], they were previously demonstrated by us to induce the epithelial to mesenchymal transition in BxPC3 [28] and they were consistent with the amount released by pancreatic tumor cells [50]. Although the low TGFβ1 dosage might be unable to induce Smad2/3 phosphorylation, never observed in our experimental conditions, a potential disruption in the TGFβ receptors might also be hypothesized [51].…”