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MECHANISMS OF SINGLE IG IL-1-RELATED RECEPTOR MEDIATED SUPPRESSION OF COLON TUMORIGENESIS

Zhao, Junjie
http://rave.ohiolink.edu/etdc/view?acc_num=case1459761067

Abstract Details

, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Inappropriate activation of the Toll-IL-1R (TL-IL-1) signaling by commensal bacteria contributes to the pathogenesis of inflammatory bowel diseases and colitis-associated cancer. SIGIRR is negative regulator of TL-IL-1 signaling. It is highly expressed in colonic epithelial cells, and Th17 cells, serving as a brake for both innate and adaptive immune system. SIGIRR deficient mice are highly susceptible to both chemical-induced and genetically based tumorigenesis, indicating that SIGIRR functions as a suppressor of colon tumorigenesis. In this treatment, we examined the cellular and molecular mechanisms of SIGIRR mediated suppression of tumor suppression. While it has been shown that epithelial-cell derived SIGIRR inhibits colon tumorigensis in mouse models, the role of SIGIRR expression in human colonic cells during the carcinogenesis remains elusive. Most SIGIRR detected in human colon cancer tissues was cytoplasmic, whereas in non-tumor tissues it was found at the cell membrane. RNA sequence analyses revealed increased expression of a SIGIRR mRNA isoform, SIGIRR¿E8, in colorectal cancer tissues compared to paired non-tumor tissues. SIGIRR¿E8 functions as a dominant negative mutant that traps full-length SIGIRR in the cytoplasm and prevents it from trafficking to the membrane. SIGIRR deficiency in T cell leads to hyper Th17 activity. Abrogation of the signaling of IL-17, the signature cytokine of Th17, attenuated the tumorigenic process by limiting the tissue repair activity. A effector downstream gene, Plet1 was identified as an IL-17 target gene that is highly induced in response to tumorigenic treatment and was required for the tissue repair process and subsequent tumorigenesis. The studies presented herein identify SIGIRR as a negative regulator of human colorectal cancer through its impact on both T cells and colonic epithelial cells.
Xiaoxia Li, Ph.D. (Advisor)
Cobb Brian, Ph.D. (Committee Chair)
Luse Donal, Ph.D. (Committee Member)
Min Booki, Ph.D. (Committee Member)
Shen Bo, M.D. (Committee Member)
Immunology
Colon cancer, innate immunity, inflammation

Recommended Citations

Citations

  • Zhao, J. (2016). MECHANISMS OF SINGLE IG IL-1-RELATED RECEPTOR MEDIATED SUPPRESSION OF COLON TUMORIGENESIS [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1459761067

    APA Style (7th edition)

  • Zhao, Junjie. MECHANISMS OF SINGLE IG IL-1-RELATED RECEPTOR MEDIATED SUPPRESSION OF COLON TUMORIGENESIS . 2016. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1459761067.

    MLA Style (8th edition)

  • Zhao, Junjie. "MECHANISMS OF SINGLE IG IL-1-RELATED RECEPTOR MEDIATED SUPPRESSION OF COLON TUMORIGENESIS ." Doctoral dissertation, Case Western Reserve University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1459761067

    Chicago Manual of Style (17th edition)

case1459761067
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© 2016, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.