IRF1 Suppresses Gastric Tumorigenesis via Dual PI3K/AKT-ERK Pathway Modulation and Functional Antagonism of Oncogenic MX2

IRF1 Suppresses Gastric Tumorigenesis via Dual PI3K/AKT-ERK Pathway Modulation and Functional Antagonism of Oncogenic MX2 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article IRF1 Suppresses Gastric Tumorigenesis via Dual PI3K/AKT-ERK Pathway Modulation and Functional Antagonism of Oncogenic MX2 Wenjing Chen, Neng Lou, Xietao Chen, Xianjing Hu, Chenchen Mao, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6435174/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Jan, 2026 Read the published version in Cellular Oncology → Version 1 posted 9 You are reading this latest preprint version Abstract Background Interferon regulatory factor 1 (IRF1) plays a crucial role in the type I interferon (IFN) response. However, its functional role and underlying mechanisms in gastric cancer (GC) remain unclear. This study aims to investigate the biological significance of IRF1 in GC progression and its potential as a therapeutic target. Methods IRF1 expression was analyzed using The Cancer Genome Atlas (TCGA) and GTEx databases, validated by immunohistochemistry (IHC) in 366 GC patients. Functional experiments, including CCK-8, Transwell migration and invasion assays, and apoptosis analysis, were conducted in GC cell lines with IRF1 overexpression or knockdown. A subcutaneous xenograft model was established to evaluate the in vivo effects of IRF1 on tumor growth. Co-immunoprecipitation and western blotting were performed to explore the molecular interactions between IRF1 and MX2, as well as its regulation of the PI3K signaling pathway. Results IRF1 expression was significantly upregulated in GC tissues compared to adjacent normal tissues and was associated with improved patient survival. Overexpression of IRF1 inhibited GC cell proliferation, migration, and invasion while promoting apoptosis, whereas IRF1 knockdown had the opposite effects. Mechanistically, IRF1 suppressed PI3K/p-AKT signaling while enhancing p-ERK1/2 activation. Moreover, IRF1 directly interacted with MX2, a protein involved in epithelial-mesenchymal transition (EMT), and this interaction was essential for suppressing MX2-mediated oncogenic activity. In vivo experiments confirmed that IRF1 overexpression significantly reduced tumor growth and metastasis. Conclusions IRF1 functions as a tumor suppressor in GC by modulating the PI3K signaling pathway and interacting with MX2 to inhibit EMT. These findings highlight IRF1 as a potential therapeutic target for GC treatment. IRF1 Gastric cancer Type I interferon response PI3K signaling MX2 EMT Tumor suppression Full Text Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterial.docx Cite Share Download PDF Status: Published Journal Publication published 13 Jan, 2026 Read the published version in Cellular Oncology → Version 1 posted Editorial decision: Revision requested 08 Aug, 2025 Reviews received at journal 21 Jul, 2025 Reviewers agreed at journal 18 Jul, 2025 Reviews received at journal 11 Jun, 2025 Reviewers agreed at journal 06 Jun, 2025 Reviewers invited by journal 06 Jun, 2025 Editor assigned by journal 20 Apr, 2025 Submission checks completed at journal 20 Apr, 2025 First submitted to journal 12 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6435174","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":468168458,"identity":"2fbea124-8912-4824-baa0-0b5f56020a00","order_by":0,"name":"Wenjing Chen","email":"","orcid":"","institution":"The First Affiliated Hospital of Wenzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wenjing","middleName":"","lastName":"Chen","suffix":""},{"id":468168459,"identity":"a7b8744a-8615-4d68-82d2-f6d8754a3891","order_by":1,"name":"Neng Lou","email":"","orcid":"","institution":"Wenzhou Medical 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MX2","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cellular-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ceon","sideBox":"Learn more about [Cellular Oncology](http://link.springer.com/journal/13402)","snPcode":"13402","submissionUrl":"https://submission.nature.com/new-submission/13402/3","title":"Cellular Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"IRF1, Gastric cancer, Type I interferon response, PI3K signaling, MX2, EMT, Tumor suppression","lastPublishedDoi":"10.21203/rs.3.rs-6435174/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6435174/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003cbr\u003e\nInterferon regulatory factor 1 (IRF1) plays a crucial role in the type I interferon (IFN) response. However, its functional role and underlying mechanisms in gastric cancer (GC) remain unclear. This study aims to investigate the biological significance of IRF1 in GC progression and its potential as a therapeutic target.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003cbr\u003e\nIRF1 expression was analyzed using The Cancer Genome Atlas (TCGA) and GTEx databases, validated by immunohistochemistry (IHC) in 366 GC patients. Functional experiments, including CCK-8, Transwell migration and invasion assays, and apoptosis analysis, were conducted in GC cell lines with IRF1 overexpression or knockdown. A subcutaneous xenograft model was established to evaluate the in vivo effects of IRF1 on tumor growth. Co-immunoprecipitation and western blotting were performed to explore the molecular interactions between IRF1 and MX2, as well as its regulation of the PI3K signaling pathway.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003cbr\u003e\nIRF1 expression was significantly upregulated in GC tissues compared to adjacent normal tissues and was associated with improved patient survival. Overexpression of IRF1 inhibited GC cell proliferation, migration, and invasion while promoting apoptosis, whereas IRF1 knockdown had the opposite effects. Mechanistically, IRF1 suppressed PI3K/p-AKT signaling while enhancing p-ERK1/2 activation. Moreover, IRF1 directly interacted with MX2, a protein involved in epithelial-mesenchymal transition (EMT), and this interaction was essential for suppressing MX2-mediated oncogenic activity. In vivo experiments confirmed that IRF1 overexpression significantly reduced tumor growth and metastasis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003cbr\u003e\nIRF1 functions as a tumor suppressor in GC by modulating the PI3K signaling pathway and interacting with MX2 to inhibit EMT. These findings highlight IRF1 as a potential therapeutic target for GC treatment.\u003c/p\u003e","manuscriptTitle":"IRF1 Suppresses Gastric Tumorigenesis via Dual PI3K/AKT-ERK Pathway Modulation and Functional Antagonism of Oncogenic MX2","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-09 13:36:02","doi":"10.21203/rs.3.rs-6435174/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-08T05:50:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-21T21:46:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"240530964380550431865111633307579369717","date":"2025-07-18T22:26:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-11T13:04:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"298059089403418713900569257187285622884","date":"2025-06-06T13:13:55+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-06T07:18:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-21T01:17:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-21T01:16:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cellular Oncology","date":"2025-04-12T14:29:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cellular-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ceon","sideBox":"Learn more about [Cellular Oncology](http://link.springer.com/journal/13402)","snPcode":"13402","submissionUrl":"https://submission.nature.com/new-submission/13402/3","title":"Cellular Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"82a7e41c-e29e-4990-ad74-af28c087e97a","owner":[],"postedDate":"June 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-19T16:48:07+00:00","versionOfRecord":{"articleIdentity":"rs-6435174","link":"https://doi.org/10.1007/s13402-025-01134-w","journal":{"identity":"cellular-oncology","isVorOnly":false,"title":"Cellular Oncology"},"publishedOn":"2026-01-13 16:29:25","publishedOnDateReadable":"January 13th, 2026"},"versionCreatedAt":"2025-06-09 13:36:02","video":"","vorDoi":"10.1007/s13402-025-01134-w","vorDoiUrl":"https://doi.org/10.1007/s13402-025-01134-w","workflowStages":[]},"version":"v1","identity":"rs-6435174","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6435174","identity":"rs-6435174","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}