Tumour-Derived Reg3A Educates Dendritic Cells to Promote Pancreatic Cancer Progression

Abstract

As a pancreatic inflammatory marker, regenerating isletderived protein 3A (Reg3A) plays a key role in inflammationassociated pancreatic carcinogenesis by promoting cell proliferation, inhibiting apoptosis, and regulating cancer cell migration and invasion. This study aimed to reveal a novel immuno-regulatory mechanism by which Reg3A modulates tumour-promoting responses during pancreatic cancer (PC) progression. In an in vitro Transwell system that allowed the direct co-culture of human peripheral blood-derived dendritic cells (DCs) and Reg3A-overexpressing/ silenced human PC cells, PC cell-derived Reg3A was found to downregulate CD80, CD83 and CD86 expression on educated DCs, increase DC endocytic function, inhibit DC-induced T lymphocyte proliferation, reduce IL-12p70 production, and enhance IL-23 production by DCs. The positive effect of tumourderived Reg3A-educated human DCs on PC progression was demonstrated in vivo by intraperitoneally transferring them into PC-implanted severe combined immunodeficiency (SCID) mice reconstituted with human T cells. A Reg3A-JAK2/STAT3 positive feedback loop was identified in DCs educated with Reg3A. In conclusion, as a tumour-derived factor, Reg3A acted to block the differentiation and maturation of the most important antigen-presenting cells, DCs, causing them to limit their potential anti-tumour responses, thus facilitating PC escape and progression.

Crosstalk between mucosal microbiota, host gene expression, and sociomedical factors in the progression of colorectal cancer

“…REG3A has been shown to have pro-tumorigenic effects, including promotion of cell proliferation, inhibition of cell apoptosis, and regulation of cancer cell migration by activating AKT and ERK1/2 pathways in gastric cancer cells 51 . REG3A has also been considered to play a key role in in ammationlinked pancreatic carcinogenesis 52,53 . Therefore, REG3A may serve as a promising therapeutic target in ACRC.…”

Increased Caveolin-2 Expression in Brain Endothelial Cells Promotes Age-Related Neuroinflammation

“…Transmigration was examined using 3-µm pore Transwell chambers (Corning, USA) coated with gelatin according to the manufacturer’s instructions ( Guo et al, 2021 ). HUVECs (Cont, Lenti-Cav-2, GFP siRNA, and Cav-2 siRNA) were seeded into the upper chambers at 2 × 10 5 cells/well for 24 h, and THP-1 cells were then added to the upper chamber of Transwells containing the endothelial cell monolayer in serum-free RPMI 1640 medium.…”

Advances in Human Dendritic Cell-Based Immunotherapy Against Gastrointestinal Cancer

“…Trefoil factor 2 (TFF2) from PC cells, a chemokine/cytokine, may attract iDCs and affect the initial stage of DC maturation, thereby contributing to the induction of immune tolerance against PC ( 45 ). As a PC-derived factor, regenerating islet-derived protein 3A (Reg3A) could inhibit the differentiation and maturation of tumor-infiltrating DCs via the Reg3A-JAK2/STAT3 signaling pathway ( 46 ). HSP70 contributed to cell survival and tumor progression.…”