Streptococcus anginosus promotes gastric inflammation, atrophy, and tumorigenesis in mice

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Pub Date : 2024-01-30 DOI:10.1016/j.cell.2024.01.004

Kaili Fu, Alvin Ho Kwan Cheung, Chi Chun Wong, Weixin Liu, Yunfei Zhou, Feixue Wang, Pingmei Huang, Kai Yuan, Olabisi Oluwabukola Coker, Yasi Pan, Danyu Chen, Nga Man Lam, Mengxue Gao, Xiang Zhang, He Huang, Ka Fai To, Joseph Jao Yiu Sung, Jun Yu

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Abstract

Streptococcus anginosus (S. anginosus) was enriched in the gastric mucosa of patients with gastric cancer (GC). Here, we show that S. anginosus colonized the mouse stomach and induced acute gastritis. S. anginosus infection spontaneously induced progressive chronic gastritis, parietal cell atrophy, mucinous metaplasia, and dysplasia in conventional mice, and the findings were confirmed in germ-free mice. In addition, S. anginosus accelerated GC progression in carcinogen-induced gastric tumorigenesis and YTN16 GC cell allografts. Consistently, S. anginosus disrupted gastric barrier function, promoted cell proliferation, and inhibited apoptosis. Mechanistically, we identified an S. anginosus surface protein, TMPC, that interacts with Annexin A2 (ANXA2) receptor on gastric epithelial cells. Interaction of TMPC with ANXA2 mediated attachment and colonization of S. anginosus and induced mitogen-activated protein kinase (MAPK) activation. ANXA2 knockout abrogated the induction of MAPK by S. anginosus. Thus, this study reveals S. anginosus as a pathogen that promotes gastric tumorigenesis via direct interactions with gastric epithelial cells in the TMPC-ANXA2-MAPK axis.

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副猪链球菌促进小鼠胃部炎症、萎缩和肿瘤发生

在胃癌（GC）患者的胃粘膜中富集了副猪链球菌（S. anginosus）。在这里，我们发现，副猪链球菌在小鼠胃中定植并诱发急性胃炎。在常规小鼠中，S. anginosus 感染可自发诱发进行性慢性胃炎、顶细胞萎缩、粘液变性和发育不良，这些结果在无菌小鼠中得到了证实。此外，在致癌物质诱导的胃肿瘤发生和 YTN16 GC 细胞异体移植中，S. anginosus 会加速 GC 的发展。一致的是，鹅膏菌破坏胃屏障功能、促进细胞增殖并抑制细胞凋亡。从机理上讲，我们发现了一种S. anginosus表面蛋白TMPC，它能与胃上皮细胞上的Annexin A2（ANXA2）受体相互作用。TMPC与ANXA2的相互作用介导了S. anginosus的附着和定植，并诱导了丝裂原活化蛋白激酶（MAPK）的激活。ANXA2 基因敲除可抑制阴沟肠杆菌对 MAPK 的诱导。因此，这项研究揭示了鹅膏菌是一种通过与胃上皮细胞在TMPC-ANXA2-MAPK轴上的直接相互作用促进胃肿瘤发生的病原体。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.