Sa2058 Hippo-YAP Signaling Pathway Modulates Stellate Cell Activation in Pancreatic Cancer and Pancreatitis

Abstract

G A A b st ra ct s for sonic hedgehog (PTCH and SMOO), GPCRs (AGTRI) and TNFaR I and II. Pancreatic mesenchymal cells were also found, using Luminex magnetic bead-based immunodetection, to be a significant source of proinflammatory cytokines IL-6 and IL-8, secreting high IL-6 levels at all times subsequent to early passages. TNF-a expression was detected only during early passage when cells exhibited an acinar-like phenotype. Interestingly, ethanol (50 mM) provided in serum free medium induced a hormetic effect, modestly stimulating cell viability associated with significant (~2-fold) elevations in HAS1, HAS2 and UGDH mRNA levels. Insulin alone (0.5-10 nM) dose-dependently suppressed HAS2 expression, but at 1 nM, modestly induced HAS1 in the presence or absence of ethanol. Ethanol-induced HAS2 gene induction was abolished in the presence of 1 nM insulin. These effects suggested some shifting between relative levels of HAS genes in response to changes in metabolic conditions. In addition, we tested the effect of conditioned medium from PDAC cell lines on HAS gene expression. The human cancer cell lines BXPC3 and MiaPaCa-2 were found to secrete high levels of IL-8, but only very low levels of IL-6 and TNF-a. Interestingly, BXPC3 and MiaPaCa2 conditioned media stimulated HAS1 and, more potently, HAS2 expression in pancreatic mesenchymal cells. We conclude that, in the tumor microenvironment, autocrine and paracrine signaling contribute to a hyaluronan synthetic phenotype that may promote tumor progression.