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dc.contributor.authorFitzgerald, Seán
dc.contributor.authorEspina, Virginia
dc.contributor.authorLiotta, Lance
dc.contributor.authorSheehan, Katherine M.
dc.contributor.authorO’Grady, Anthony
dc.contributor.authorCummins, Robert
dc.contributor.authorO’Kennedy, Richard
dc.contributor.authorKay, Elaine W.
dc.contributor.authorKijanka, Gregor S.
dc.date.accessioned2019-12-04T13:47:04Z
dc.date.available2019-12-04T13:47:04Z
dc.date.issued2018-04-10
dc.identifier.citationFitzgerald, Seán, Espina, Virginia, Liotta, Lance, Sheehan, Katherine M., O’Grady, Anthony, Cummins, Robert, O’Kennedy, Richard, Kay, Elaine W., Kijanka, Gregor S. (2018). Stromal TRIM28-associated signaling pathway modulation within the colorectal cancer microenvironment. Journal of Translational Medicine, 16(1), 89. doi: 10.1186/s12967-018-1465-zen_IE
dc.identifier.issn1479-5876
dc.identifier.urihttp://hdl.handle.net/10379/15614
dc.description.abstractBackground Stromal gene expression patterns predict patient outcomes in colorectal cancer. TRIM28 is a transcriptional co-repressor that regulates an abundance of genes through the KRAB domain family of transcription factors. We have previously shown that stromal expression of TRIM28 is a marker of disease relapse and poor survival in colorectal cancer. Here, we perform differential epithelium-stroma proteomic network analyses to characterize signaling pathways associated with TRIM28 within the tumor microenvironment. Methods Reverse phase protein arrays were generated from laser capture micro-dissected carcinoma and stromal cells from fresh frozen colorectal cancer tissues. Phosphorylation and total protein levels were measured for 30 cancer-related signaling pathway endpoints. Strength and direction of associations between signaling endpoints were identified using Spearman’s rank-order correlation analysis and compared to TRIM28 levels. Expression status of TRIM28 in tumor epithelium and stromal fibroblasts was assessed using IHC in formalin fixed tissue and the epithelium to stroma protein expression ratio method. Results We found distinct proteomic networks in the epithelial and stromal compartments which were linked to expression levels of TRIM28. Low levels of TRIM28 in tumor stroma (high epithelium: stroma ratio) were found in 10 out of 19 cases. Upon proteomic network analyses, these stromal high ratio cases revealed moderate signaling pathway similarity exemplified by 76 significant Spearman correlations (ρ ≥ 0.75, p ≤ 0.01). Furthermore, low levels of stromal TRIM28 correlated with elevated MDM2 levels in tumor epithelium (p = 0.01) and COX-2 levels in tumor stroma (p = 0.002). Low TRIM28 epithelium to stroma ratios were associated with elevated levels of caspases 3 and 7 in stroma (p = 0.041 and p = 0.036) and an increased signaling pathway similarity in stromal cells with 81 significant Spearman correlations (ρ ≥ 0.75, p ≤ 0.01). Conclusions By dissecting TRIM28-associated pathways in stromal fibroblasts and epithelial tumor cells, we performed comprehensive proteomic analyses of molecular networks within the tumor microenvironment. We found modulation of several signaling pathways associated with TRIM28, which may be attributed to the pleiotropic properties of TRIM28 through its translational suppression of the family of KRAB domain transcription factors in tumor stromal compartments.en_IE
dc.description.sponsorshipThis material is based upon works supported by the Irish Cancer Society Research (CRF10KIJ), Science Foundation Ireland (10/CE/B1821), the Pathological Society (VF 2013/04/01), the Orla Benson Award (Dublin City University) and the Mater Foundation. There are no competing interests on the part of any of the authors listed. We gratefully acknowledge the help of Dr. Joanna Fay and our surgical colleagues in Beaumont Hospital, Dublin.en_IE
dc.language.isoenen_IE
dc.publisherBMC (part of Springer Nature)en_IE
dc.relation.ispartofJournal of translational medicineen
dc.subjectTRIM28en_IE
dc.subjectColorectal canceren_IE
dc.subjectEpitheliumen_IE
dc.subjectStromaen_IE
dc.subjectPrognosisen_IE
dc.subjecttumor antigenen_IE
dc.titleStromal TRIM28-associated signaling pathway modulation within the colorectal cancer microenvironmenten_IE
dc.typeArticleen_IE
dc.date.updated2019-11-27T11:32:02Z
dc.identifier.doi10.1186/s12967-018-1465-z
dc.local.publishedsourcehttps://doi.org/10.1186/s12967-018-1465-zen_IE
dc.description.peer-reviewedpeer-reviewed
dc.contributor.funderIrish Cancer Societyen_IE
dc.contributor.funderScience Foundation Irelanden_IE
dc.internal.rssid17361162
dc.local.contactSeán Fitzgerald, Physiology, School Of Medicine, Nui Galway. Email: sean.fitzgerald@nuigalway.ie
dc.local.copyrightcheckedYes
dc.local.versionSUBMITTED
dcterms.projectinfo:eu-repo/grantAgreement/SFI/SFI Short Term Travel Fellowship (STTF)/10/CE/B1821 - STTF 11/IE/Carbon nanofibre-based biosensor platform for advanced diagnostic devices/en_IE
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