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dc.contributor.authorSheng, YH
dc.contributor.authorHe, Y
dc.contributor.authorHasnain, SZ
dc.contributor.authorWang, R
dc.contributor.authorTong, H
dc.contributor.authorClarke, DT
dc.contributor.authorLourie, R
dc.contributor.authorOancea, I
dc.contributor.authorWong, KY
dc.contributor.authorLumley, JW
dc.contributor.authorFlorin, TH
dc.contributor.authorSutton, P
dc.contributor.authorHooper, JD
dc.contributor.authorMcMillan, NA
dc.contributor.authorMcGuckin, MA
dc.date.accessioned2018-07-11T03:12:06Z
dc.date.available2018-07-11T03:12:06Z
dc.date.issued2017
dc.identifier.issn0950-9232
dc.identifier.doi10.1038/onc.2016.241
dc.identifier.urihttp://hdl.handle.net/10072/100649
dc.description.abstractMUC13 is a transmembrane mucin glycoprotein that is over produced by many cancers, although its functions are not fully understood. Nuclear factor-κB (NF-κB) is a key transcription factor promoting cancer cell survival, but therapeutically targeting this pathway has proved difficult because NF-κB has pleiotropic functions. Here, we report that MUC13 prevents colorectal cancer cell death by promoting two distinct pathways of NF-kB activation, consequently upregulating BCL-XL. MUC13 promoted tumor necrosis factor (TNF)-induced NF-κB activation by interacting with TNFR1 and the E3 ligase, cIAP1, to increase ubiquitination of RIPK1. MUC13 also promoted genotoxin-induced NF-κB activation by increasing phosphorylation of ATM and SUMOylation of NF-κB essential modulator. Moreover, elevated expression of cytoplasmic MUC13 and NF-κB correlated with colorectal cancer progression and metastases. Our demonstration that MUC13 enhances NF-κB signaling in response to both TNF and DNA-damaging agents provides a new molecular target for specific inhibition of NF-κB activation. As proof of principle, silencing MUC13 sensitized colorectal cancer cells to killing by cytotoxic drugs and inflammatory signals and abolished chemotherapy-induced enrichment of CD133+ CD44+ cancer stem cells, slowed xenograft growth in mice, and synergized with 5-fluourouracil to induce tumor regression. Therefore, these data indicate that combining chemotherapy and MUC13 antagonism could improve the treatment of metastatic cancers.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherNature Publishing Group
dc.relation.ispartofpagefrom1
dc.relation.ispartofpageto14
dc.relation.ispartofjournalOncogene
dc.subject.fieldofresearchOncology and Carcinogenesis not elsewhere classified
dc.subject.fieldofresearchClinical Sciences
dc.subject.fieldofresearchOncology and Carcinogenesis
dc.subject.fieldofresearchcode111299
dc.subject.fieldofresearchcode1103
dc.subject.fieldofresearchcode1112
dc.titleMUC13 protects colorectal cancer cells from death by activating the NF-κB pathway and is a potential therapeutic target
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttp://creativecommons.org/licenses/by-nc-sa/4.0/
dc.description.versionVersion of Record (VoR)
gro.description.notepublicThis publication has been entered into Griffith Research Online as an Advanced Online Version.
gro.rights.copyright© The Author(s) 2017. This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
gro.hasfulltextFull Text
gro.griffith.authorMcMillan, Nigel
gro.griffith.authorClarke, Daniel


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