Cooperative participation of CagA and NFATc1 in the pathogenesis of antibiotics-responsive gastric MALT lymphoma

Hui-Jen Tsai; Kun-Huei Yeh; Chung-Wu Lin; Ming-Shiang Wu; Jyh-Ming Liou; Ping-Ning Hsu; Yi-Shin Zeng; Ming-Feng Wei; Chia-Tung Shun; Hsiu-Po Wang; Li-Tzong Chen; Ann-Lii Cheng; Sung-Hsin Kuo

doi:10.1186/s12935-024-03552-6

Cooperative participation of CagA and NFATc1 in the pathogenesis of antibiotics-responsive gastric MALT lymphoma

Cancer Cell Int. 2024 Nov 18;24(1):383. doi: 10.1186/s12935-024-03552-6.

Authors

Hui-Jen Tsai^{1

2

3}, Kun-Huei Yeh^{4

5

6}, Chung-Wu Lin^{7

8}, Ming-Shiang Wu⁹, Jyh-Ming Liou^{9

10}, Ping-Ning Hsu⁹, Yi-Shin Zeng^{4

5}, Ming-Feng Wei^{4

5}, Chia-Tung Shun⁷, Hsiu-Po Wang⁹, Li-Tzong Chen^{1

2

3}, Ann-Lii Cheng^{4

5

6

9

11}, Sung-Hsin Kuo^{12

13

14}

Affiliations

¹ National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
² Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
³ Department of Oncology, National Cheng-Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁴ Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan South Rd, Taipei, Taiwan.
⁵ Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan.
⁶ Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
⁷ Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
⁸ Department of Pathology and Laboratory Medicine, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan.
⁹ Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
¹⁰ Department of Internal Medicine, National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan.
¹¹ Department of Medical Oncology, National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan.
¹² Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan South Rd, Taipei, Taiwan. shkuo101@ntu.edu.tw.
¹³ Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan. shkuo101@ntu.edu.tw.
¹⁴ Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan. shkuo101@ntu.edu.tw.

Abstract

Background: This study aimed to explore whether cytotoxin-associated gene A (CagA) can inhibit cell cycle progression by activating nuclear factor of activated T cells (NFAT) in lymphoma B cells and contribute to Helicobacter pylori eradication (HPE) responsiveness (complete remission [CR] after HPE) in gastric mucosa-associated lymphoid tissue (MALT) lymphoma.

Materials and methods: We co-cultured three B-lymphoma cell lines (MA-1, OCI-Ly3, and OCI-Ly7) with HP strains (derived from HPE-responsive gastric MALT lymphoma) and evaluated the expression patterns of CagA, phosphorylated (p)-CagA (CagA^P-Tyr), and CagA-signaling molecules, cell-cycle inhibitors, p-NFATc1 (Ser¹⁷²), and NFATc1 using western blotting. Furthermore, we evaluated the association between nuclear NFATc1 expression in the tumor cells of 91 patients who received first-line HPE (59 patients with HPE responsiveness and 32 without HPE responsiveness) and HPE responsiveness and CagA expression in tumor cells.

Results: In HP strains co-cultured with B cell lymphoma cell lines, CagA was translocated to the nucleus through tyrosine phosphorylation (CagA^P-Tyr) and simultaneously dephosphorylated NFATc1, subsequently causing nuclear NFATc1 translocation and stimulating the expression of p-SHP-2/p-ERK/Bcl-xL. Activated NFATc1 causes G1 cell cycle retardation in both MA-1 and OCI-Ly3 cells by triggering p21 and p27 production. Nuclear NFATc1 localization was significantly associated with the presence of CagA in gastric MALT lymphomas (80% [41/51] vs. 33% [13/40]; p < 0.001) and with HPE responsiveness (73% [43/59] vs. 25% [8/32]; p < 0.001). Patients exhibiting both the presence of CagA and nuclear NFATc1 localization responded more rapidly to HPE than those without (median interval to CR, 4.00 vs. 6.00 months, p = 0.003).

Conclusions: Our findings indicated that CagA and NFATc1 cooperatively participate in the lymphomagenesis of HPE-responsive gastric MALT lymphoma.

Keywords: Helicobacter pylori; CagA; MALT lymphoma; NFATc1; Stomach.

Abstract

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