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.
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.
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
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
Legal entity responsible for the study
Ministry of Science and Technology, Taiwan
All authors have declared no conflicts of interest.