METTL14-mediated m6A Modification of COL3A1 mRNA Inhibits Gastric Cancer Metastasis via Recognition by YTHDF2

METTL14-mediated m6A Modification of COL3A1 mRNA Inhibits Gastric Cancer Metastasis via Recognition by YTHDF2 | 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 Article METTL14-mediated m6A Modification of COL3A1 mRNA Inhibits Gastric Cancer Metastasis via Recognition by YTHDF2 Junfu Guo, Linlin Zhao, JiLuan Wang, Han Yang, Mingyue Cai This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8011182/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Gastric cancer metastasis remains a leading cause of cancer-related mortality, yet its underlying regulatory mechanisms are not fully understood. The RNA N6-methyladenosine (m⁶A) writer METTL14 serves a context-dependent role in tumor progression. In this study, we identify METTL14 as a crucial metastasis suppressor in gastric cancer and clarify its specific mechanism of action. Through integrated MeRIP-seq and functional analyses, we discovered that METTL14 directs the m⁶A-dependent degradation of COL3A1 mRNA, a previously unrecognized key driver of gastric cancer progression. METTL14 knockdown markedly enhanced tumor invasion, migration, proliferation, and stem-like properties in vitro and promoted metastasis in vivo, which were all effectively reversed by concurrent COL3A1 silencing. Mechanistically, METTL14-mediated suppression of COL3A1 required recognition by the m⁶A reader YTHDF2, establishing a complete METTL14/YTHDF2-COL3A1 regulatory axis. Our findings not only resolve the context-dependent role of METTL14 in gastric cancer but also reveal a therapeutically targetable axis for combating metastasis. Biological sciences/Cancer/Gastrointestinal cancer/Gastric cancer Biological sciences/Molecular biology/Epigenetics/Gene silencing Biological sciences/Cell biology/Cell migration/Extracellular matrix Gastric cancer METTL14 COL3A1 m⁶A YTHDF2 Full Text Additional Declarations There is NO conflict of interest to disclose. Supplementary Files SupplementaryFigure.pdf Supplementary Figure S1 Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8011182","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":539851825,"identity":"f61ff507-f630-4608-bf6f-4cc58509aef9","order_by":0,"name":"Junfu Guo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0UlEQVRIiWNgGAWjYJACAwYGOQZ+BuaGA6RoMWaQbGAkQQsDSIvBAcYG4tTKRyQfKObdYZC4+fjBxsO8bXcY+Nu7E/BqMbyRlmDMe8YgcduZxAaglmcMEmfObsCvZUaOgTFv25/EbQfAWg4zGEjkEqUF6LD+h0RqkZeAatkgQawtBjzPEgznthkYz7jxsOHgnHOHeQj6Rb49+ZjB2zYD2f7+5MMf3pQdluNv7yVgywEGNgMYh4mHgYEHr3KwLQ0MzA9gHMYfBNWPglEwCkbBSAQA42JNdHXPIBkAAAAASUVORK5CYII=","orcid":"","institution":"Liaoning University of Traditional Chinese Medicine","correspondingAuthor":true,"prefix":"","firstName":"Junfu","middleName":"","lastName":"Guo","suffix":""},{"id":539851826,"identity":"b83d05d2-a774-479e-99b0-0c0f11662632","order_by":1,"name":"Linlin Zhao","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Linlin","middleName":"","lastName":"Zhao","suffix":""},{"id":539851827,"identity":"61faae0a-882c-4a37-af3e-385b7b9e0dbc","order_by":2,"name":"JiLuan Wang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"JiLuan","middleName":"","lastName":"Wang","suffix":""},{"id":539851828,"identity":"fb03865d-fdad-4430-8a7e-5fa2f3cee17d","order_by":3,"name":"Han Yang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Han","middleName":"","lastName":"Yang","suffix":""},{"id":539851829,"identity":"951a325a-b88d-4b73-91f4-0f9ef5077620","order_by":4,"name":"Mingyue Cai","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Mingyue","middleName":"","lastName":"Cai","suffix":""}],"badges":[],"createdAt":"2025-11-02 13:20:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8011182/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8011182/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":95940892,"identity":"ac70a6dd-e2a1-4c88-94ba-784557449f81","added_by":"auto","created_at":"2025-11-14 16:18:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11950498,"visible":true,"origin":"","legend":"","description":"","filename":"Result.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8011182/v1/c2b756fc6f70bdb53427c777.pdf"},{"id":95940891,"identity":"a0375828-3d31-435b-a701-0463935a1e82","added_by":"auto","created_at":"2025-11-14 16:18:44","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":328234,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8011182/v1/d8c322691f661826b67bc47c.pdf"},{"id":96245172,"identity":"3e93fab9-7d14-482c-b016-eee50b622a29","added_by":"auto","created_at":"2025-11-19 07:20:00","extension":"json","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6289,"visible":true,"origin":"","legend":"","description":"","filename":"ONC202503319.json","url":"https://assets-eu.researchsquare.com/files/rs-8011182/v1/a2cc8a172ac0c11765ffc176.json"},{"id":95940888,"identity":"cd191165-c1e3-4fe0-b22b-65e2a87d4883","added_by":"auto","created_at":"2025-11-14 16:18:44","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":435831,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8011182/v1/11ecdb140c5b600416013b81.pdf"},{"id":96454414,"identity":"7f0c9ee6-32f0-4fbb-97ea-2dfb185963b4","added_by":"auto","created_at":"2025-11-21 10:02:43","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":12217774,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8011182/v1_covered_855d9e93-40ed-4b9b-b319-f013223eb43a.pdf"},{"id":95940889,"identity":"e3f9e74b-5d0d-4af5-a01b-9a779375ddbe","added_by":"auto","created_at":"2025-11-14 16:18:44","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":435831,"visible":true,"origin":"","legend":"Supplementary Figure S1","description":"","filename":"SupplementaryFigure.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8011182/v1/8d4e062ed1962992c7185ca7.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"METTL14-mediated m6A Modification of COL3A1 mRNA Inhibits Gastric Cancer Metastasis via Recognition by YTHDF2","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Gastric cancer, METTL14, COL3A1, m⁶A, YTHDF2","lastPublishedDoi":"10.21203/rs.3.rs-8011182/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8011182/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Gastric cancer metastasis remains a leading cause of cancer-related mortality, yet its underlying regulatory mechanisms are not fully understood. The RNA N6-methyladenosine (m⁶A) writer METTL14 serves a context-dependent role in tumor progression. In this study, we identify METTL14 as a crucial metastasis suppressor in gastric cancer and clarify its specific mechanism of action. Through integrated MeRIP-seq and functional analyses, we discovered that METTL14 directs the m⁶A-dependent degradation of COL3A1 mRNA, a previously unrecognized key driver of gastric cancer progression. METTL14 knockdown markedly enhanced tumor invasion, migration, proliferation, and stem-like properties in vitro and promoted metastasis in vivo, which were all effectively reversed by concurrent COL3A1 silencing. Mechanistically, METTL14-mediated suppression of COL3A1 required recognition by the m⁶A reader YTHDF2, establishing a complete METTL14/YTHDF2-COL3A1 regulatory axis. Our findings not only resolve the context-dependent role of METTL14 in gastric cancer but also reveal a therapeutically targetable axis for combating metastasis.","manuscriptTitle":"METTL14-mediated m6A Modification of COL3A1 mRNA Inhibits Gastric Cancer Metastasis via Recognition by YTHDF2","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-14 16:18:40","doi":"10.21203/rs.3.rs-8011182/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"857a0441-1c09-4cf0-a1f4-8a5cbf114694","owner":[],"postedDate":"November 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":57420626,"name":"Biological sciences/Cancer/Gastrointestinal cancer/Gastric cancer"},{"id":57420627,"name":"Biological sciences/Molecular biology/Epigenetics/Gene silencing"},{"id":57420628,"name":"Biological sciences/Cell biology/Cell migration/Extracellular matrix"}],"tags":[],"updatedAt":"2025-11-20T16:28:51+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-14 16:18:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8011182","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8011182","identity":"rs-8011182","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}