Establishment of a Gene Expression Signature for Colitis-Associated Colorectal Cancer to Assess Cancer-Promoting Effects of Standard IBD Treatments

Establishment of a Gene Expression Signature for Colitis-Associated Colorectal Cancer to Assess Cancer-Promoting Effects of Standard IBD Treatments | 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 Establishment of a Gene Expression Signature for Colitis-Associated Colorectal Cancer to Assess Cancer-Promoting Effects of Standard IBD Treatments Sarah Pashapour, Nesa Kazemifard, Shaghayegh Baradaran Ghavami, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8753984/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background: Inflammatory bowel disease, particularly ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract that can progress to colitis-associated colorectal cancer. In addition to disease-related risk, certain pharmacological therapies used in UC management may further increase the likelihood of malignancies, including colorectal cancer. This study was conducted to identify novel biomarkers associated with carcinogenesis and early detection of CAC in patients with ulcerative colitis, using integrative bioinformatics approaches. Methods: Differential gene expression analysis was performed on microarray datasets. Genes commonly dysregulated in UC, sporadic colorectal cancer, and CAC, as well as CAC-specific genes, were identified as potential biomarkers. The expression levels of selected candidate genes were subsequently quantified by quantitative real-time PCR in colonic tissue samples obtained from UC patients receiving the studied pharmacological treatments, untreated UC patients, and healthy control individuals. Results: The genes SERPINE1 , COL1A1 , MMP9 , IL1B , ANXA5 , CAV1 , TLR2 , and VCAM1 were selected as candidate biomarkers. Long-term use of 5-aminosalicylic acid for more than five years resulted in a significant upregulation of COL1A1 , ANXA5 , and VCAM1 . Treatment with corticosteroids and immunomodulatory agents significantly increased the expression of IL1B and SERPINE1 , whereas anti-TNF therapy led to a significant increase only in CAV1 expression. Conclusions: Anti-TNF therapy was associated with significant upregulation of CAV1 , a gene involved in membrane signaling, endothelial integrity, and inflammatory regulation, and uniquely showed reduced expression of pro-inflammatory and adhesion-related genes such as IL1B and VCAM1 compared with untreated patients. In contrast, long-term treatment with 5-ASA, corticosteroids, and immunomodulatory agents did not reduce the expression of any analyzed genes and instead increased the expression of multiple candidates. These treatments were characterized by upregulation of IL1B , SERPINE1 , COL1A1 , MMP9 , ANXA5 , TLR2 , and VCAM1 suggest amplified inflammatory cell infiltration and epithelial damage, creating a microenvironment conducive to chronic inflammation, disease recurrence, and progression toward colitis-associated colorectal cancer. Overall, prolonged use of 5-ASA, corticosteroids, and immunomodulatory therapies appears to promote inflammation-driven carcinogenic pathways, limiting their suitability for long-term UC management, whereas anti-TNF therapy demonstrates a comparatively protective molecular profile by attenuating key inflammatory and immune pathways and may represent reduced contribution to CAC progression. Inflammatory bowel disease Ulcerative colitis Colitis-associated colorectal cancer Differential gene expression analysis IBD treatment Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterial.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 07 May, 2026 Reviews received at journal 07 Apr, 2026 Reviews received at journal 03 Apr, 2026 Reviewers agreed at journal 31 Mar, 2026 Reviewers agreed at journal 26 Mar, 2026 Reviewers invited by journal 18 Mar, 2026 Editor assigned by journal 16 Mar, 2026 Editor invited by journal 19 Feb, 2026 Submission checks completed at journal 18 Feb, 2026 First submitted to journal 14 Feb, 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-8753984","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":609004872,"identity":"7f84649a-71b1-4a7e-998c-019272cff753","order_by":0,"name":"Sarah Pashapour","email":"","orcid":"","institution":"Isfahan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"","lastName":"Pashapour","suffix":""},{"id":609004873,"identity":"4aa20a3b-eee6-497e-9a9f-456a1c5170a8","order_by":1,"name":"Nesa Kazemifard","email":"","orcid":"","institution":"Shahid Beheshti University of Medical 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Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Inflammatory bowel disease, Ulcerative colitis, Colitis-associated colorectal cancer, Differential gene expression analysis, IBD treatment","lastPublishedDoi":"10.21203/rs.3.rs-8753984/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8753984/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eInflammatory bowel disease, particularly ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract that can progress to colitis-associated colorectal cancer. In addition to disease-related risk, certain pharmacological therapies used in UC management may further increase the likelihood of malignancies, including colorectal cancer. This study was conducted to identify novel biomarkers associated with carcinogenesis and early detection of CAC in patients with ulcerative colitis, using integrative bioinformatics approaches.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eDifferential gene expression analysis was performed on microarray datasets. Genes commonly dysregulated in UC, sporadic colorectal cancer, and CAC, as well as CAC-specific genes, were identified as potential biomarkers. The expression levels of selected candidate genes were subsequently quantified by quantitative real-time PCR in colonic tissue samples obtained from UC patients receiving the studied pharmacological treatments, untreated UC patients, and healthy control individuals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe genes \u003cem\u003eSERPINE1\u003c/em\u003e, \u003cem\u003eCOL1A1\u003c/em\u003e, \u003cem\u003eMMP9\u003c/em\u003e, \u003cem\u003eIL1B\u003c/em\u003e, \u003cem\u003eANXA5\u003c/em\u003e, \u003cem\u003eCAV1\u003c/em\u003e, \u003cem\u003eTLR2\u003c/em\u003e, and \u003cem\u003eVCAM1\u003c/em\u003e were selected as candidate biomarkers. Long-term use of 5-aminosalicylic acid for more than five years resulted in a significant upregulation of \u003cem\u003eCOL1A1\u003c/em\u003e, \u003cem\u003eANXA5\u003c/em\u003e, and \u003cem\u003eVCAM1\u003c/em\u003e. Treatment with corticosteroids and immunomodulatory agents significantly increased the expression of \u003cem\u003eIL1B\u003c/em\u003e and \u003cem\u003eSERPINE1\u003c/em\u003e, whereas anti-TNF therapy led to a significant increase only in \u003cem\u003eCAV1\u003c/em\u003eexpression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eAnti-TNF therapy was associated with significant upregulation of \u003cem\u003eCAV1\u003c/em\u003e, a gene involved in membrane signaling, endothelial integrity, and inflammatory regulation, and uniquely showed reduced expression of pro-inflammatory and adhesion-related genes such as \u003cem\u003eIL1B and VCAM1\u003c/em\u003e compared with untreated patients. In contrast, long-term treatment with 5-ASA, corticosteroids, and immunomodulatory agents did not reduce the expression of any analyzed genes and instead increased the expression of multiple candidates. These treatments were characterized by upregulation of \u003cem\u003eIL1B\u003c/em\u003e, \u003cem\u003eSERPINE1\u003c/em\u003e, \u003cem\u003eCOL1A1\u003c/em\u003e, \u003cem\u003eMMP9\u003c/em\u003e, \u003cem\u003eANXA5\u003c/em\u003e, \u003cem\u003eTLR2\u003c/em\u003e, and \u003cem\u003eVCAM1\u003c/em\u003e suggest amplified inflammatory cell infiltration and epithelial damage, creating a microenvironment conducive to chronic inflammation, disease recurrence, and progression toward colitis-associated colorectal cancer. Overall, prolonged use of 5-ASA, corticosteroids, and immunomodulatory therapies appears to promote inflammation-driven carcinogenic pathways, limiting their suitability for long-term UC management, whereas anti-TNF therapy demonstrates a comparatively protective molecular profile by attenuating key inflammatory and immune pathways and may represent reduced contribution to CAC progression.\u003c/p\u003e","manuscriptTitle":"Establishment of a Gene Expression Signature for Colitis-Associated Colorectal Cancer to Assess Cancer-Promoting Effects of Standard IBD Treatments","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-23 15:52:41","doi":"10.21203/rs.3.rs-8753984/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-07T07:36:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-08T00:55:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-03T17:07:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"226587721516274983361579110365199650402","date":"2026-03-31T11:37:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"223485727601549568490191338269577061673","date":"2026-03-26T17:05:15+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-18T21:34:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-16T08:12:02+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-20T04:46:42+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-19T00:08:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Gastroenterology","date":"2026-02-14T07:56:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"12603b46-181d-4aec-99ea-955c4e921e7a","owner":[],"postedDate":"March 23rd, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-07T07:36:34+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-17T21:38:13+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-23 15:52:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8753984","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8753984","identity":"rs-8753984","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}