SH2D2A as a VEGF pathway-related oncogene driving colorectal cancer through mTOR activation

SH2D2A as a VEGF pathway-related oncogene driving colorectal cancer through mTOR activation | 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 SH2D2A as a VEGF pathway-related oncogene driving colorectal cancer through mTOR activation Rongdi Wang, Yutong Wang, Xu Guo, Meng Xu, Jianfeng Wang, Chengzhong Xing This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9084283/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 9 You are reading this latest preprint version Abstract Background : Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, largely due to tumor metastasis and the lack of reliable prognostic biomarkers and therapeutic targets. The vascular endothelial growth factor (VEGF) pathway plays a pivotal role in CRC progression, yet its regulatory network remains incompletely understood. Methods : Differentially expressed genes (DEGs) between CRC and adjacent normal tissues were identified from TCGA and GEO databases. Functional enrichment analyses (GO/KEGG) were performed to explore biological processes and signaling pathways. Univariate Cox regression and LASSO regression analyses were employed to construct a prognostic risk signature based on VEGF pathway-related genes. The signature was validated internally in the TCGA cohort and externally in the GSE39582 dataset. Functional experiments, including CCK-8, colony formation, Transwell, and wound healing assays, were conducted to investigate the role of SH2D2A in CRC cells. Xenograft mouse models were used for in vivo validation. Molecular docking was performed to identify potential SH2D2A inhibitors. Results : A total of 84 VEGF pathway-related DEGs were identified, with enrichment in VEGF, Ras, HIF-1, and focal adhesion signaling pathways. An 11-gene prognostic signature (ADD2, BDNF, BGN, CD1B, CXCL1, MMP10, OXTR, PGF, PLCG2, SH2D2A, SPHK1) was constructed, which effectively stratified CRC patients into high-risk (poor prognosis) and low-risk (favorable prognosis) groups. The signature demonstrated robust predictive performance in both internal (AUC at 1-, 3-, and 5-year: 0.726, 0.703, and 0.671, respectively) and external validation cohorts. SH2D2A was identified as a key oncogenic driver, showing significant upregulation in CRC tissues. Functional assays revealed that SH2D2A knockdown suppressed CRC cell proliferation, colony formation, migration, and invasion, while re-expression rescued these malignant phenotypes. Mechanistically, SH2D2A promoted CRC progression through dual activation of the mTOR and VEGFA signaling pathways. Xenograft models confirmed that SH2D2A knockout significantly inhibited tumor growth in vivo. Molecular docking identified Adavivint as a potential SH2D2A inhibitor, which effectively suppressed CRC malignant behaviors in vitro and tumor growth in vivo without significant systemic toxicity. Conclusions : This study establishes a VEGF pathway-related prognostic signature for CRC risk stratification and identifies SH2D2A as a novel oncogene in CRC, with its effects potentially linked to mTOR signaling and VEGFA regulation. Targeting SH2D2A with Adavivint represents a promising therapeutic strategy for CRC, offering new insights into both prognostic assessment and targeted therapy. Colorectal cancer VEGF pathway SH2D2A prognostic signature mTOR VEGFA Adavivint molecular docking Full Text Additional Declarations No competing interests reported. Supplementary Files WBrawdata3.docx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 12 May, 2026 Reviews received at journal 27 Apr, 2026 Reviews received at journal 25 Apr, 2026 Reviewers agreed at journal 22 Apr, 2026 Reviewers agreed at journal 21 Apr, 2026 Reviewers invited by journal 16 Apr, 2026 Editor assigned by journal 30 Mar, 2026 Submission checks completed at journal 25 Mar, 2026 First submitted to journal 25 Mar, 2026 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. 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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-9084283","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":627824644,"identity":"7e779cef-3bc8-4caf-a6d9-234b1c892733","order_by":0,"name":"Rongdi Wang","email":"","orcid":"","institution":"Central Hospital of Dalian University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Rongdi","middleName":"","lastName":"Wang","suffix":""},{"id":627824645,"identity":"95e452a4-895f-414b-93ee-85b76138d5c8","order_by":1,"name":"Yutong Wang","email":"","orcid":"","institution":"Dalian Medical 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The vascular endothelial growth factor (VEGF) pathway plays a pivotal role in CRC progression, yet its regulatory network remains incompletely understood.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: Differentially expressed genes (DEGs) between CRC and adjacent normal tissues were identified from TCGA and GEO databases. Functional enrichment analyses (GO/KEGG) were performed to explore biological processes and signaling pathways. Univariate Cox regression and LASSO regression analyses were employed to construct a prognostic risk signature based on VEGF pathway-related genes. The signature was validated internally in the TCGA cohort and externally in the GSE39582 dataset. Functional experiments, including CCK-8, colony formation, Transwell, and wound healing assays, were conducted to investigate the role of SH2D2A in CRC cells. Xenograft mouse models were used for in vivo validation. Molecular docking was performed to identify potential SH2D2A inhibitors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: A total of 84 VEGF pathway-related DEGs were identified, with enrichment in VEGF, Ras, HIF-1, and focal adhesion signaling pathways. An 11-gene prognostic signature (ADD2, BDNF, BGN, CD1B, CXCL1, MMP10, OXTR, PGF, PLCG2, SH2D2A, SPHK1) was constructed, which effectively stratified CRC patients into high-risk (poor prognosis) and low-risk (favorable prognosis) groups. The signature demonstrated robust predictive performance in both internal (AUC at 1-, 3-, and 5-year: 0.726, 0.703, and 0.671, respectively) and external validation cohorts. SH2D2A was identified as a key oncogenic driver, showing significant upregulation in CRC tissues. Functional assays revealed that SH2D2A knockdown suppressed CRC cell proliferation, colony formation, migration, and invasion, while re-expression rescued these malignant phenotypes. 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Targeting SH2D2A with Adavivint represents a promising therapeutic strategy for CRC, offering new insights into both prognostic assessment and targeted therapy.\u003c/p\u003e","manuscriptTitle":"SH2D2A as a VEGF pathway-related oncogene driving colorectal cancer through mTOR activation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-24 19:25:32","doi":"10.21203/rs.3.rs-9084283/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-12T07:11:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-27T13:15:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-25T14:17:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"21398306519715597449502893331967177473","date":"2026-04-22T11:19:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"324019849818687767693480461238417611221","date":"2026-04-21T05:05:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-16T10:51:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-30T09:13:53+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-25T14:33:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"Discover Oncology","date":"2026-03-25T14:11:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"discover-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dion","sideBox":"Learn more about [Discover Oncology](https://www.springer.com/12672)","snPcode":"","submissionUrl":"","title":"Discover Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"dda600ea-7c49-4c52-9ec0-eaf3371844ee","owner":[],"postedDate":"April 24th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-12T07:11:28+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-12T07:24:22+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-24 19:25:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9084283","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9084283","identity":"rs-9084283","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}