{"title":"Cooperative participation of CagA and NFATc1 in the pathogenesis of antibiotics-responsive gastric MALT lymphoma.","authors":"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","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Materials and methods: </strong>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<sup>P-Tyr</sup>), and CagA-signaling molecules, cell-cycle inhibitors, p-NFATc1 (Ser<sup>172</sup>), 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.</p><p><strong>Results: </strong>In HP strains co-cultured with B cell lymphoma cell lines, CagA was translocated to the nucleus through tyrosine phosphorylation (CagA<sup>P-Tyr</sup>) 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).</p><p><strong>Conclusions: </strong>Our findings indicated that CagA and NFATc1 cooperatively participate in the lymphomagenesis of HPE-responsive gastric MALT lymphoma.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"24 1","pages":"383"},"PeriodicalIF":5.3000,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11575159/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Cell International","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12935-024-03552-6","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
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 (CagAP-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 (CagAP-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.
背景：本研究旨在探讨细胞毒素相关基因A（CagA）是否能通过激活淋巴瘤B细胞中的活化T细胞核因子（NFAT）来抑制细胞周期的进展，并促使胃黏膜相关淋巴组织（MALT）淋巴瘤对幽门螺杆菌根除（HPE）反应性（HPE后完全缓解[CR]）：我们将三种B淋巴瘤细胞系（MA-1、OCI-Ly3和OCI-Ly7）与HP菌株（来源于HPE反应性胃MALT淋巴瘤）共培养，并使用Western印迹法评估了CagA、磷酸化（p）-CagA（CagAP-Tyr）、CagA信号分子、细胞周期抑制剂、p-NFATc1（Ser172）和NFATc1的表达模式。此外，我们还评估了91例一线HPE患者（59例有HPE反应性，32例无HPE反应性）的肿瘤细胞核NFATc1表达与HPE反应性和肿瘤细胞中CagA表达之间的关联：结果：在与B细胞淋巴瘤细胞系共培养的HPE菌株中，CagA通过酪氨酸磷酸化（CagAP-Tyr）转位至细胞核，同时使NFATc1去磷酸化，随后引起NFATc1核转位，刺激p-SHP-2/p-ERK/Bcl-xL的表达。活化的NFATc1通过触发p21和p27的产生，导致MA-1和OCI-Ly3细胞的G1细胞周期延缓。在胃MALT淋巴瘤中，核NFATc1定位与CagA的存在显著相关（80% [41/51] vs. 33% [13/40]; p 结论：我们的研究结果表明，CagA和NFATc1在胃MALT淋巴瘤中的定位与CagA的存在显著相关：我们的研究结果表明，CagA和NFATc1共同参与了HPE反应性胃MALT淋巴瘤的淋巴致病过程。
期刊介绍：
Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques.
The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors.
Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.
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