Figure 6.

Schematic model of possible signal transduction stimulated by CRP in BON1 cells. In pNEN microenvironment, special immunological cells and hepatocytes are one source of CRP and/or IL-6. The other source of CRP and IL-6 is BON1 or QGP1 cells. The binding of IL-6 to its ligand-binding receptor initiates activation of AKT, which in turn phosphorylates and activates STAT3 transcription factors. Activated STAT3 binds to specific sites in the target gene promoters inducing transcription of BCL-2 and MMP-9, thus resulting in proliferation and metastasis (invasion/migration) of pancreatic neuroendocrine tumor cells, as well as the expression and secretion of CRP. Secreted CRP may exert its effects by internalization either through an unknown receptor (?) or via endocytosis. It activates ERK as well as IL-6 secretion, thereby leading to proliferation and metastasis in pancreatic neuroendocrine tumor cells.