{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T14:47:22Z","timestamp":1776782842294,"version":"3.51.2"},"reference-count":49,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T00:00:00Z","timestamp":1772668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>To assess the therapeutic relevance of BRIP1 in gastric cancer (GC), we examine its functional role in conferring resistance to anoikis within GC cells and elucidate the oncogenic signaling pathways modulated by BRIP1. By integrating the Cancer Genome Atlas (TCGA) and Gene Set Enrichment Analysis (GSEA) databases with Least Absolute Shrinkage and Selection Operator (LASSO) regression, a novel risk score to stratify GC patients based on prognosis was generated, and a significantly differentially expressed gene, BRIP1, was validated through reverse transcription quantitative polymerase chain reaction (RT-qPCR). Protein expression associated with apoptosis, cell cycle, and epithelial-mesenchymal transformation (EMT) was quantified via RT-qPCR and Western blot (WB). 5-Ethynyl-2\u2032-deoxyuridine (EdU) and cell counting kit-8 (CCK-8) assays were conducted to quantify proliferative activity. The protein level in axillary tumor tissues of nude mice was detected by immunohistochemistry (IHC). We established an eight-gene anoikis-related prognostic risk assessment model (DUSP1, VCAN, P3H2, TXNIP, BRIP1, FGD6, GPX3, and RLN2) for GC. Multivariate Cox regression confirmed the risk score as an independent prognostic factor. Among these genes, BRIP1 showed significant differential expression between tumor and normal tissues, as well as normal gastric mucosal epithelial cells and GC cells. Mechanistically, BRIP1 conferred anoikis resistance to GC cells by suppressing the generation of reactive oxygen species (ROS). We found that the PI3K inhibitor LY294002 counteracted BRIP1-driven oncogenic effects, which was evidenced by restored expression of key regulators governing apoptosis, cell cycle progression, and EMT, in addition to suppressed proliferation in GC cells. BRIP1 is postulated to function upstream of the PI3K\/Akt signaling cascade. This study establishes a risk scoring model and identifies BRIP1 as a potential prognostic marker for GC.<\/jats:p>","DOI":"10.3390\/ijms27052409","type":"journal-article","created":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T13:11:22Z","timestamp":1772716282000},"page":"2409","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Role and Mechanism of BRIP1 in Anoikis Resistance of Gastric Cancer"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5831-1203","authenticated-orcid":false,"given":"Shijiao","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ai","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medical, Southeast University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liyang","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuanli","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Shen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaobing","family":"Shen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/S0140-6736(20)31288-5","article-title":"Gastric cancer","volume":"396","author":"Smyth","year":"2020","journal-title":"Lancet"},{"key":"ref_2","first-page":"229","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":"ref_3","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s13045-025-01698-y","article-title":"The current landscape of gastric cancer and gastroesophageal junction cancer diagnosis and treatment in China: A comprehensive nationwide cohort analysis","volume":"18","author":"Chen","year":"2025","journal-title":"J. Hematol. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3481","DOI":"10.1016\/j.bbamcr.2013.06.026","article-title":"Anoikis molecular pathways and its role in cancer progression","volume":"1833","author":"Paoli","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1002\/path.3000","article-title":"Anoikis: An emerging hallmark in health and diseases","volume":"226","author":"Taddei","year":"2012","journal-title":"J. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1016\/j.bcp.2008.07.023","article-title":"Anoikis: A necessary death program for anchorage-dependent cells","volume":"76","author":"Chiarugi","year":"2008","journal-title":"Biochem. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8908","DOI":"10.18632\/aging.205005","article-title":"TIMP1 shapes an immunosuppressive microenvironment by regulating anoikis to promote the progression of clear cell renal cell carcinoma","volume":"15","author":"Li","year":"2023","journal-title":"Aging"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"797","DOI":"10.21037\/atm-21-1631","article-title":"Gastric cancer-associated microRNA expression signatures: Integrated bioinformatics analysis, validation, and clinical significance","volume":"9","author":"Liu","year":"2021","journal-title":"Ann. Transl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1615\/CritRevOncog.2016016955","article-title":"Anoikis and EMT: Lethal \u201cLiaisons\u201d during Cancer Progression","volume":"21","author":"Cao","year":"2016","journal-title":"Crit. Rev. Oncog."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Manfioletti, G., and Fedele, M. (2023). Epithelial-Mesenchymal Transition (EMT). Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241411386"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1146\/annurev-pathol-020117-043854","article-title":"Epithelial Mesenchymal Transition in Tumor Metastasis","volume":"13","author":"Mittal","year":"2018","journal-title":"Annu. Rev. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1242\/jcs.120907","article-title":"Mechanisms that link the oncogenic epithelial-mesenchymal transition to suppression of anoikis","volume":"126","author":"Frisch","year":"2013","journal-title":"J. Cell Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e358","DOI":"10.1016\/S1470-2045(21)00343-0","article-title":"Novel therapeutic strategies: Targeting epithelial-mesenchymal transition in colorectal cancer","volume":"22","author":"Zhang","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1002\/1878-0261.12425","article-title":"The FZD7-TWIST1 axis is responsible for anoikis resistance and tumorigenesis in ovarian carcinoma","volume":"13","author":"Tan","year":"2019","journal-title":"Mol. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.freeradbiomed.2022.10.271","article-title":"Shear stress enhances anoikis resistance of cancer cells through ROS and NO suppressed degeneration of Caveolin-1","volume":"193","author":"Chen","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"479","DOI":"10.3109\/10715761003667554","article-title":"Reactive oxygen species in cancer","volume":"44","author":"Liou","year":"2010","journal-title":"Free Radic. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1038\/s41568-021-00435-0","article-title":"The role of ROS in tumour development and progression","volume":"22","author":"Cheung","year":"2022","journal-title":"Nat. Rev. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6299","DOI":"10.1158\/0008-5472.CAN-12-4082","article-title":"Epithelial-mesenchymal transition and tumor suppression are controlled by a reciprocal feedback loop between ZEB1 and Grainyhead-like-2","volume":"73","author":"Cieply","year":"2013","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/s41580-023-00629-4","article-title":"Mechanisms of BCL-2 family proteins in mitochondrial apoptosis","volume":"24","author":"Czabotar","year":"2023","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.biocel.2012.10.009","article-title":"EZH2 is regulated by ERK\/AKT and targets integrin alpha2 gene to control Epithelial-Mesenchymal Transition and anoikis in colon cancer cells","volume":"45","author":"Ferraro","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1186\/s12964-023-01183-4","article-title":"Anoikis resistance\u2014Protagonists of breast cancer cells survive and metastasize after ECM detachment","volume":"21","author":"Dai","year":"2023","journal-title":"Cell Commun. Signal."},{"key":"ref_22","first-page":"101947","article-title":"Exploration of the role of drug resistance-associated anoikis-related genes in HER2-Negative breast cancer through bioinformatics analysis","volume":"41","author":"Wu","year":"2025","journal-title":"Biochem. Biophys. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1007\/s12013-024-01634-w","article-title":"Bioinformatics-based Prognosis Effect of Ferroptosis-related Genes on Gastric Cancer","volume":"83","author":"Wang","year":"2025","journal-title":"Cell Biochem. Biophys."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1002\/iid3.414","article-title":"Bioinformatics analysis of the prognosis and biological significance of VCAN in gastric cancer","volume":"9","author":"Huang","year":"2021","journal-title":"Immun. Inflamm. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1038\/sj.bjc.6605042","article-title":"The prolyl 3-hydroxylases P3H2 and P3H3 are novel targets for epigenetic silencing in breast cancer","volume":"100","author":"Shah","year":"2009","journal-title":"Br. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s12957-022-02877-8","article-title":"Multimolecular characteristics and role of BRCA1 interacting protein C-terminal helicase 1 (BRIP1) in human tumors: A pan-cancer analysis","volume":"21","author":"Wang","year":"2023","journal-title":"World J. Surg. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3296","DOI":"10.1007\/s12094-023-03180-y","article-title":"A nine-gene signature as prognostic biomarker in gastric cancer by bioinformatics analysis","volume":"25","author":"Wang","year":"2023","journal-title":"Clin. Transl. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/s11658-024-00626-1","article-title":"PTBP1 knockdown impairs autophagy flux and inhibits gastric cancer progression through TXNIP-mediated oxidative stress","volume":"29","author":"Wang","year":"2024","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zeng, J., Li, M., Shi, H., and Guo, J. (2021). Upregulation of FGD6 Predicts Poor Prognosis in Gastric Cancer. Front. Med., 8.","DOI":"10.3389\/fmed.2021.672595"},{"key":"ref_30","first-page":"1194","article-title":"Gpx3 prevents migration and invasion in gastric cancer by targeting NF\u043aB\/Wnt5a\/JNK signaling","volume":"12","author":"Cai","year":"2019","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Liu, D., Xu, Y., Fang, Y., and Hu, K. (2022). Development of a Novel Immune-Related Gene Signature to Predict Prognosis and Immunotherapeutic Efficiency in Gastric Cancer. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.885553"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1055\/s-0043-122385","article-title":"Artificial intelligence may help in predicting the need for additional surgery after endoscopic resection of T1 colorectal cancer","volume":"50","author":"Ichimasa","year":"2018","journal-title":"Endoscopy"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1136\/gutjnl-2019-319292","article-title":"Artificial intelligence-guided tissue analysis combined with immune infiltrate assessment predicts stage III colon cancer outcomes in PETACC08 study","volume":"69","author":"Reichling","year":"2020","journal-title":"Gut"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1200\/JCO.2015.65.9128","article-title":"Development and Validation of a Radiomics Nomogram for Preoperative Prediction of Lymph Node Metastasis in Colorectal Cancer","volume":"34","author":"Huang","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"djv214","DOI":"10.1093\/jnci\/djv214","article-title":"Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women with Ovarian Cancer","volume":"107","author":"Ramus","year":"2015","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5315","DOI":"10.1007\/s11033-020-05612-2","article-title":"New germline mutations in non-BRCA genes among breast cancer women of Mongoloid origin","volume":"47","author":"Gervas","year":"2020","journal-title":"Mol. Biol. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1158\/1940-6207.CAPR-20-0316","article-title":"BRIP1, a Gene Potentially Implicated in Familial Colorectal Cancer Type, X","volume":"14","author":"Garre","year":"2021","journal-title":"Cancer Prev. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"508","DOI":"10.21147\/j.issn.1000-9604.2020.04.08","article-title":"Characteristics of cancer susceptibility genes mutations in 282 patients with gastric adenocarcinoma","volume":"32","author":"Ji","year":"2020","journal-title":"Chin. J. Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.3748\/wjg.v26.i11.1197","article-title":"Landscape of BRIP1 molecular lesions in gastrointestinal cancers from published genomic studies","volume":"26","author":"Voutsadakis","year":"2020","journal-title":"World J. Gastroenterol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Katheeja, M.N., Das, S.P., Das, R., and Laha, S. (2023). BRCA1 interactors, RAD50 and BRIP1, as prognostic markers for triple-negative breast cancer severity. Front. Genet., 14.","DOI":"10.3389\/fgene.2023.1035052"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4560","DOI":"10.7150\/ijbs.69933","article-title":"TCF7L2 promotes anoikis resistance and metastasis of gastric cancer by transcriptionally activating PLAUR","volume":"18","author":"Zhang","year":"2022","journal-title":"Int. J. Biol. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.mad.2007.09.005","article-title":"Increased ROS generation in subsets of OGG1 knockout fibroblast cells","volume":"128","author":"Bacsi","year":"2007","journal-title":"Mech. Ageing Dev."},{"key":"ref_43","first-page":"1023","article-title":"Reduced-gliotoxin induces ROS-mediated anoikis in human colorectal cancer cells","volume":"52","author":"Chen","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4819","DOI":"10.7150\/jca.58670","article-title":"Upregulation of V-ATPase by STAT3 Activation Promotes Anoikis Resistance and Tumor Metastasis","volume":"12","author":"Adeshakin","year":"2021","journal-title":"J. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1038\/s41419-018-0953-7","article-title":"NADPH oxidase 4 regulates anoikis resistance of gastric cancer cells through the generation of reactive oxygen species and the induction of EGFR","volume":"9","author":"Du","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e2500136","DOI":"10.1002\/smll.202500136","article-title":"SERPINE1 Facilitates Metastasis in Gastric Cancer Through Anoikis Resistance and Tumor Microenvironment Remodeling","volume":"21","author":"Wang","year":"2025","journal-title":"Small"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e22202","DOI":"10.1002\/jbt.22202","article-title":"Caveolin-1 contributes to anoikis resistance in human gastric cancer SGC-7901 cells via regulating Src-dependent EGFR-ITGB1 signaling","volume":"32","author":"Wang","year":"2018","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"11127","DOI":"10.1038\/s41598-017-11769-x","article-title":"Hypoxia-induced ANGPTL4 sustains tumour growth and anoikis resistance through different mechanisms in scirrhous gastric cancer cell lines","volume":"7","author":"Baba","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"109648","DOI":"10.1016\/j.cbi.2021.109648","article-title":"A-24, a steroidal saponin from Allium chinense, induced apoptosis, autophagy and migration inhibition in p53 wild-type and p53-deficient gastric cancer cells","volume":"348","author":"Xu","year":"2021","journal-title":"Chem. Biol. Interact."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/5\/2409\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T13:14:08Z","timestamp":1772716448000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/5\/2409"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,5]]},"references-count":49,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27052409"],"URL":"https:\/\/doi.org\/10.3390\/ijms27052409","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,5]]}}}