{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T05:47:22Z","timestamp":1785822442589,"version":"3.56.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018806","name":"Department of Science and Technology of Hubei Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100018806","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003819","name":"Natural Science Foundation of Hubei Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003819","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Gastric cancer (GC) remains a major cause of cancer-related mortality, highlighting the need to clarify the stromal and post-translational mechanisms underlying its progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated single-cell RNA sequencing, independent transcriptomic cohorts, clinical tissue analyses, functional assays, co-immunoprecipitation (Co-IP), multiple immunofluorescence labeling, and a xenograft model to investigate the cellular distribution, biological function, and mechanisms of regulation for matrix metalloproteinase 2 (MMP2) in GC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Single-cell analysis of paired tumor and adjacent normal tissues suggested an increased relative abundance of fibroblast populations and higher extracellular matrix-associated activity in GC tissues. MMP2 was preferentially expressed in cancer-associated fibroblasts, particularly in transcriptionally defined universal fibroblast-like and myofibroblastic CAF states. Trajectory analysis further suggested that the MMP2-high universal fibroblast-like population occupies an early and potentially transitional position along the fibroblast-state continuum. These findings were supported by an independent single-cell dataset, TCGA-STAD analysis, and tissue staining. In CAF\u2013gastric cancer cell co-culture assays, CAFs enhanced tumor-cell migration and invasion, while modulation of the FBXW7\u2013MMP2 axis altered these phenotypes. MMP2 overexpression promoted GC cell proliferation, migration, and invasion, whereas MMP2 silencing had the opposite effects. Mechanistically, FBXW7 interacted with the intracellular pool of MMP2, enhanced its K48-linked polyubiquitination, and reduced MMP2 protein stability through a proteasome-dependent process. FBXW7 overexpression attenuated MMP2-associated malignant phenotypes\n                      <jats:italic>in vitro<\/jats:italic>\n                      and restrained MMP2-driven tumor growth\n                      <jats:italic>in vivo<\/jats:italic>\n                      . Clinical tissue analyses further showed an inverse association between FBXW7 and MMP2 expression, while elevated MMP2 was associated with unfavorable survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings identify MMP2-high fibroblast states as an important stromal feature of GC and reveal FBXW7-associated regulation of intracellular MMP2 stability as a potential therapeutic vulnerability.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1877833","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T05:35:58Z","timestamp":1785821758000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["FBXW7 suppresses gastric cancer development and progression via ubiquitination-mediated degradation of MMP2"],"prefix":"10.3389","volume":"17","author":[{"given":"Changjiang","family":"Hao","sequence":"first","affiliation":[{"name":"Hubei Key Laboratory for Translational Research in Traditional Chinese Medicine, Hubei Selenium and Human Health Institute, Department of Colorectal and Anal Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Hubei Minzu University","place":["Enshi, China"]},{"name":"Hubei Provincial Key Lab of Selenium Resources and Bioapplications","place":["Enshi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengping","family":"Jiang","sequence":"additional","affiliation":[{"name":"Modern Research Center for Traditional Chinese Medicine, Key Laboratory of Research and Utilization of Bioactive Components in Famous shanxi Medicinal Materials, shanxi University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songpu","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Li","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory for Translational Research in Traditional Chinese Medicine, Hubei Selenium and Human Health Institute, Department of Colorectal and Anal Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Hubei Minzu University","place":["Enshi, China"]},{"name":"Division of Nephrology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, No.158 Wuyang Avenue","place":["Enshi City, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jilv","family":"Peng","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory for Translational Research in Traditional Chinese Medicine, Hubei Selenium and Human Health Institute, Department of Colorectal and Anal Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Hubei Minzu University","place":["Enshi, China"]},{"name":"Hubei Provincial Key Lab of Selenium Resources and Bioapplications","place":["Enshi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Qin","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory for Translational Research in Traditional Chinese Medicine, Hubei Selenium and Human Health Institute, Department of Colorectal and Anal Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Hubei Minzu University","place":["Enshi, China"]},{"name":"Hubei Provincial Key Lab of Selenium Resources and Bioapplications","place":["Enshi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlan","family":"Li","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory for Translational Research in Traditional Chinese Medicine, Hubei Selenium and Human Health Institute, Department of Colorectal and Anal Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Hubei Minzu University","place":["Enshi, China"]},{"name":"Hubei Provincial Key Lab of Selenium Resources and Bioapplications","place":["Enshi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Tan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, School of Life Sciences, Hubei University","place":["#368 Youyi Road, Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongsheng","family":"Jiang","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory for Translational Research in Traditional Chinese Medicine, Hubei Selenium and Human Health Institute, Department of Colorectal and Anal Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Hubei Minzu University","place":["Enshi, China"]},{"name":"Hubei Provincial Key Lab of Selenium Resources and Bioapplications","place":["Enshi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture","place":["Enshi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoquan","family":"Huang","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory for Translational Research in Traditional Chinese Medicine, Hubei Selenium and Human Health Institute, Department of Colorectal and Anal Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Hubei Minzu University","place":["Enshi, China"]},{"name":"Hubei Provincial Key Lab of Selenium Resources and Bioapplications","place":["Enshi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/b978-0-443-15609-0.00017-9","article-title":"Gastric cancer","volume":"396","author":"Smyth","year":"2020","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B3","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1097\/cm9.0000000000002626","article-title":"Global burden prediction of gastric cancer during demographic transition from 2020 to 2040","volume":"136","author":"Yan","year":"2023","journal-title":"Chin Med J (Engl)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/js9.0000000000001054","article-title":"Global, regional, and national burdens of early onset pancreatic cancer in adolescents and adults aged 15-49 years from 1990 to 2019 based on the Global Burden of Disease Study 2019: a cross-sectional study","volume":"110","author":"Li","year":"2024","journal-title":"Int J Surg"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-025-02267-3","article-title":"Distinct age-related effects of homologous recombination deficiency on genomic profiling and treatment efficacy in gastric cancer","volume":"60","author":"Maki","year":"2025","journal-title":"J Gastroenterol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2025.189350","article-title":"Tumor immune microenvironment remodeling\u00a0after neoadjuvant therapy in gastric cancer: Update and new challenges","volume":"1880","author":"Sun","year":"2025","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"B7","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1038\/s41419-024-07250-z","article-title":"SP-1-activated LINC01016 overexpression promotes gastric cancer invasion and metastasis through inhibiting EIF4A3-mediated MMP9 mRNA decay","volume":"16","author":"Sun","year":"2025","journal-title":"Cell Death Dis"},{"key":"B8","doi-asserted-by":"publisher","first-page":"16449","DOI":"10.1038\/s41598-025-97983-4","article-title":"Tumor microenvironment modulation by SERPINE1 increases radioimmunotherapy in murine model of gastric cancer","volume":"15","author":"Zaheer","year":"2025","journal-title":"Sci Rep"},{"key":"B9","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.actbio.2024.08.055","article-title":"Enhancing melanoma therapy by modulating the immunosuppressive microenvironment with an MMP-2 sensitive and nHA\/GNE co-encapsulated hydrogel","volume":"188","author":"Chen","year":"2024","journal-title":"Acta Biomater"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1021\/acsami.4c18502","article-title":"Tumor microenvironment-responsive nanodrug for embolotherapy and enhanced chemotherapy","volume":"17","author":"Zheng","year":"2025","journal-title":"ACS Appl Mater Interfaces"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2025.03.008","article-title":"Alcaligenes faecalis induces intestinal T helper-17 cells by enhancing Rorc transcription through E3 ligase Trim21-mediated Fbxw7 degradation","volume":"58","author":"Shen","year":"2025","journal-title":"Immunity"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2025.03.032","article-title":"Aberrant ubiquitination causing liver cancer: The ADRM1-DeltaEx9- FBXW7 connection","volume":"83","author":"Calvisi","year":"2025","journal-title":"J Hepatol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.can-18-4032","article-title":"SCF(FBXW7)\/GSK3beta-mediated GFI1 degradation suppresses proliferation of gastric cancer cells","volume":"79","author":"Kuai","year":"2019","journal-title":"Cancer Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.69454","article-title":"The lncRNA BDNF-AS\/WDR5\/FBXW7 axis mediates ferroptosis in gastric cancer peritoneal metastasis by regulating VDAC3 ubiquitination","volume":"18","author":"Huang","year":"2022","journal-title":"Int J Biol Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/5055684","article-title":"The lncRNA SEMA3B-AS1\/HMGB1\/FBXW7 axis mediates the peritoneal metastasis of gastric cancer by regulating BGN protein ubiquitination","volume":"2022","author":"Huang","year":"2022","journal-title":"Oxid Med Cell Longev"},{"key":"B16","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1186\/s13046-024-03220-7","article-title":"MDM2 drives resistance to Osimertinib by contextually disrupting FBW7-mediated destruction of MCL-1 protein in EGFR mutant NSCLC","volume":"43","author":"Liu","year":"2024","journal-title":"J Exp Clin Cancer Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-025-02349-z","article-title":"NAP1L1 degradation by FBXW7 reduces the deubiquitination of HDGF-p62 signaling to stimulate autophagy and induce primary cisplatin chemosensitivity in nasopharyngeal carcinoma","volume":"24","author":"Gong","year":"2025","journal-title":"Mol Cancer"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2024.119827","article-title":"E3 ubiquitin ligases and deubiquitinases in colorectal cancer: Emerging molecular insights and therapeutic opportunities","volume":"1871","author":"Kumar","year":"2024","journal-title":"Biochim Biophys Acta Mol Cell Res"},{"key":"B19","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1186\/s13046-025-03400-z","article-title":"ANXA1 promotes intrahepatic cholangiocarcinoma proliferation and growth by regulating glutamine metabolism through GOT1 stabilization","volume":"44","author":"Gong","year":"2025","journal-title":"J Exp Clin Cancer Res"},{"key":"B20","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1186\/s13046-025-03404-9","article-title":"Tumor cell-intrinsic BIN1 deficiency promotes the immunosuppression and impedes ferroptosis of non-small cell lung cancer via G3BP1-mediated degradation of STAT1","volume":"44","author":"Wang","year":"2025","journal-title":"J Exp Clin Cancer Res"},{"key":"B21","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1186\/s12967-022-03361-3","article-title":"Phosphorylated ATF1 at Thr184 promotes metastasis and regulates MMP2 expression in gastric cancer","volume":"20","author":"Li","year":"2022","journal-title":"J Transl Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202000608r","article-title":"ATP5B promotes the metastasis and growth of gastric cancer by activating the FAK\/AKT\/MMP2 pathway","volume":"35","author":"Wang","year":"2021","journal-title":"FASEB J"},{"key":"B23","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s40709-021-00154-5","article-title":"Circ_0000620 acts as an oncogenic factor in gastric cancer through regulating MMP2 expression via sponging miR-671-5p","volume":"28","author":"Ren","year":"2021","journal-title":"J Biol Res (Thessalon)"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s13402-025-01053-w","article-title":"High extracellular matrix stiffness upregulates TNNT1 to awaken dormant tumor cells in liver metastatic niches of gastric cancer","volume":"48","author":"Ji","year":"2025","journal-title":"Cell Oncol (Dordr)"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2025.1600960","article-title":"Exploring the anti-gastric cancer mechanisms of Diosgenin through integrated network analysis, bioinformatics, single-cell sequencing, and cell experiments","volume":"16","author":"Yun","year":"2025","journal-title":"Front Pharmacol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.34133\/research.0716","article-title":"CX3CR1(+) monocytes\/macrophages promote regional immune injury in mesangial proliferative glomerulonephritis through crosstalk with activated mesangial cells","volume":"8","author":"Zhang","year":"2025","journal-title":"Res (Wash D C)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1186\/s12967-025-06551-x","article-title":"Single-cell transcriptomic analysis deciphers the inflammatory microenvironment characterized by CXCL9+ fibroblasts and ACKR1+ endothelial cells in immune-related myocarditis","volume":"23","author":"Sun","year":"2025","journal-title":"J Transl Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-025-01308-4","article-title":"Immune microenvironment in hepatocellular carcinoma: From pathogenesis to immunotherapy","volume":"22","author":"Seyhan","year":"2025","journal-title":"Cell Mol Immunol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"4317","DOI":"10.1016\/j.celrep.2019.04.052","article-title":"Dissecting the single-cell transcriptome network underlying gastric premalignant lesions and early gastric cancer","volume":"30","author":"Zhang","year":"2020","journal-title":"Cell Rep"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1125-8","article-title":"Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma","volume":"27","author":"Wang","year":"2021","journal-title":"Nat Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03549-5","article-title":"Cross-tissue organization of the fibroblast lineage","volume":"593","author":"Buechler","year":"2021","journal-title":"Nature"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0238-1","article-title":"A framework for advancing our understanding of cancer-associated fibroblasts","volume":"20","author":"Sahai","year":"2020","journal-title":"Nat Rev Cancer"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2024.116821","article-title":"A patent review of SCF E3 ligases inhibitors for cancer: Structural design, pharmacological activities and structure-activity relationship","volume":"278","author":"Zeng","year":"2024","journal-title":"Eur J Med Chem"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00310.2024","article-title":"Clitocine enhances the drug sensitivity of colon cancer cells by promoting FBXW7-mediated MCL-1 degradation via inhibiting the A2B\/cAMP\/ERK axis","volume":"327","author":"Ruan","year":"2024","journal-title":"Am J Physiol Cell Physiol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2009.03662.x","article-title":"Cleaved high molecular weight kininogen inhibits tube formation of endothelial progenitor cells via suppression of matrix metalloproteinase 2","volume":"8","author":"Wu","year":"2010","journal-title":"J Thromb Haemost"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.107.151456","article-title":"PECAM-1: a multi-functional molecule in inflammation and vascular biology","volume":"27","author":"Woodfin","year":"2007","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1084\/jem.178.2.449","article-title":"PECAM-1 is required for transendothelial migration of leukocytes.pdf","volume":"178","author":"Muller","year":"1993","journal-title":"J Exp Med"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1877833\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T05:36:01Z","timestamp":1785821761000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1877833\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":37,"alternative-id":["10.3389\/fimmu.2026.1877833"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1877833","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]},"article-number":"1877833"}}