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CagA and NFAT co-operatively participate in the lymphomagenesis of gastric MALT lymphoma

Date

08 Oct 2016

Session

Poster Display

Presenters

Sung-Hsin Kuo

Citation

Annals of Oncology (2016) 27 (6): 313-327. 10.1093/annonc/mdw375

Authors

S. Kuo1, H. Tsai2, K. Yeh1, C. Lin3, Y. Zeng1, M. Wu4, P. Hsu4, L. Chen5, A. Cheng1

Author affiliations

  • 1 Department Of Oncology, National Taiwan University Hospital and National Taiwan University Cancer Center, 100 - Taipei/TW
  • 2 National Institute Of Cancer Research, National Health Research Institutes, Tainan/TW
  • 3 Department Of Pathology, National Taiwan University Hospital and National Taiwan University Cancer Center, 100 - Taipei/TW
  • 4 Department Of Internal Medicine, National Taiwan University Hospital and National Taiwan University Cancer Center, 100 - Taipei/TW
  • 5 National Institute Of Cancer Research, National Health Research Institutes, 704 - Tainan/TW
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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.

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