Prevention of colitis-associated cancer by selective targeting of immunoproteasome subunit LMP7

Research output: Contribution to journalJournal article – Annual report year: 2017Researchpeer-review

  • Author: Vachharajani, Niyati

    University of Marburg, Germany

  • Author: Joeris, Thorsten

    Mucosal Immunology, Division of Immunology & Vaccinology, National Veterinary Institute, Technical University of Denmark, Kemitorvet, 2800, Kgs. Lyngby, Denmark

  • Author: Luu, Maik

    University of Marburg, Germany

  • Author: Hartmann, Sabrina

    University of Marburg, Germany

  • Author: Pautz, Sabine

    University of Marburg, Germany

  • Author: Jenike, Elena

    University of Marburg, Germany

  • Author: Pantazis, Georgios

    University of Marburg, Germany

  • Author: Prinz, Immo

    Hannover Medical School, Germany

  • Author: Hofer, Markus J

    University of Marburg, Germany

  • Author: Steinhoff, Ulrich

    University of Marburg, Germany

  • Author: Visekruna, Alexander

    University of Marburg, Germany

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Chronic inflammation is a well-known risk factor in development of intestinal tumorigenesis, although the exact mechanisms underlying development of colitis-associated cancer (CAC) still remain obscure. The activity and function of immunoproteasome has been extensively analyzed in the context of inflammation and infectious diseases. Here, we show that the proteasomal immunosubunit LMP7 plays an essential role in development of CAC. Mice devoid of LMP7 were resistant to chronic inflammation and formation of neoplasia, and developed virtually no tumors after AOM/DSS treatment. Our data reveal that LMP7 deficiency resulted in reduced expression of pro-tumorigenic chemokines CXCL1, CXCL2 and CXCL3 as well as adhesion molecule VCAM-1. As a consequence, an impaired recruitment and activity of tumor-infiltrating leukocytes resulting in decreased secretion of cytokines IL-6 and TNF-α was observed. Further, the deletion or pharmacological inhibition of LMP7 and consequent blockade of NF-κB abrogated the production of IL-17A, which possesses a strong carcinogenic activity in the gut. Moreover, in vivo administration of the selective LMP7 inhibitor ONX-0914 led to a marked reduction of tumor numbers in wild-type (WT) mice. Collectively, we identified the immunoproteasome as a crucial mediator of inflammation-driven neoplasia highlighting a novel potential therapeutic approach to limit colonic tumorigenesis.
Original languageEnglish
JournalOncoTarget
Number of pages13
ISSN1949-2553
DOIs
Publication statusPublished - 2017
CitationsWeb of Science® Times Cited: No match on DOI

    Research areas

  • NF-κB, colon cancer, immunoproteasome, inflammation

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