Abstract 3852
Background
Previous studies revealed that in gastric epithelial cell, CagA can inhibit progression of the cell cycle through activation of nuclear factor of activated T-cell (NFAT) and NFAT-dependent genes, such as p21. We recently reported that CagA and its signaling molecules, p-SHP-2, p-ERK, and Bcl-xL were associated with H. pylori (HP) dependence of gastric mucosa-associated lymphoid tissue lymphoma (MALToma). In this study, we further assessed if CagA and NFAT co-operatively participate in the lymphomagenesis of gastric MALToma.
Methods
HP strains were cultured from patients with HP-dependent gastric MALToma. We co-cultured gastric epithelial cell, MA-1 cell (t(14;18)(q32;q21)/IGH-MALT1-positive B-cell lymphoma), and Pfeiffer cell (diffuse large B-cell lymphoma) with HP strains and further evaluated the expression pattern of CagA, CagA-signaling molecules and NFATc1 using western blotting and confocal immunoinfluence. The cell cycle, p21, and p27 were analyzed. The association between CagA and NFATc1 expression in malignant B cells and tumor response to HP eradication therapy (HPE) was further evaluated in 67 patients with stage IE/IIE1 gastric MALToma.
Results
NFATc1 was activated by CagA in HP-co-cultured gastric epithelial cells and MA-1 cells, but NFATc1 was not activated in HP-co-cultured Pfeiffer cell. In HP-co-cultured MA-1 cells, we revealed that CagA up-regulated the expression of p-SHP-2, p-ERK, and Bcl-xL, and CagA-inducing nuclear NFATc1 translocation was abolished by inhibiting calcineurin using cyclosporine A. The HP-co-cultured MA-1 cell exhibited G1 cell-cycle retardation through the activation of NFATc1, p21, and p27. The nuclear NFATc1 expression rate was significantly higher in HP-dependent than in HP-independent tumors (70.0% [28/40] vs. 29.6% [8/27]; P = 0.001). Similarly, CagA expression was closely correlated with the HP-dependence of these tumors (P
Conclusions
Our results indicate that CagA can derive direct NFAT signaling cooperate in HP-induced lymphomagenesis of gastric MALToma, and the co-expression of CagA and NFATc1 is clinically and biologically significant.
Clinical trial identification
NA
Legal entity responsible for the study
N/A
Funding
Ministry of Science and Technology, Taiwan
Disclosure
All authors have declared no conflicts of interest.