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    MUC13 protects colorectal cancer cells from death by activating the NF-kappa B pathway and is a potential therapeutic target

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    22
    Author
    Sheng, YH; He, Y; Hasnain, SZ; Wang, R; Tong, H; Clarke, DT; Lourie, R; Oancea, I; Wong, KY; Lumley, JW; ...
    Date
    2017-02-02
    Source Title
    Oncogene
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Sutton, Philip; McGuckin, Michael; Clarke, Daniel
    Affiliation
    Paediatrics (RCH)
    Microbiology and Immunology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Sheng, Y. H., He, Y., Hasnain, S. Z., Wang, R., Tong, H., Clarke, D. T., Lourie, R., Oancea, I., Wong, K. Y., Lumley, J. W., Florin, T. H., Sutton, P., Hooper, J. D., McMillan, N. A. & McGuckin, M. A. (2017). MUC13 protects colorectal cancer cells from death by activating the NF-kappa B pathway and is a potential therapeutic target. ONCOGENE, 36 (5), pp.700-713. https://doi.org/10.1038/onc.2016.241.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/259508
    DOI
    10.1038/onc.2016.241
    Abstract
    MUC13 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.

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