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Selective targeting of immunoproteasome subunit LMP7 prevents colitis-associated carcinogenesis
Chronic inflammation is a well-known risk factor for the development of colonic tumorigenesis. In this study, we show that the immunoproteasome (iP) subunit LMP7 plays a crucial role in the progression of colitis-associated carcinogenesis (CAC). The activity and function of the iP complex has been e...
সংরক্ষণ করুন:
| প্রধান লেখক: | |
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| অন্যান্য লেখক: | |
| বিন্যাস: | Dissertation |
| ভাষা: | ইংরেজি |
| প্রকাশিত: |
Philipps-Universität Marburg
2016
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| বিষয়গুলি: | |
| অনলাইন ব্যবহার করুন: | পিডিএফ এ সম্পূর্ন পাঠ |
| ট্যাগগুলো: |
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| সংক্ষিপ্ত: | Chronic inflammation is a well-known risk factor for the development of colonic tumorigenesis. In this study, we show that the immunoproteasome (iP) subunit LMP7 plays a crucial role in the progression of colitis-associated carcinogenesis (CAC). The activity and function of the iP complex has been extensively studied in the context of MHC class I-coupled antigen presentation, inflammation and infectious diseases.
Here we show that the absence of LMP7 exerts a protective effect, since the LMP7-deficient mice fail to develop a full scale of carcinogenesis after CAC induction with AOM/DSS treatment. Our findings demonstrate that LMP7 deficiency results in reduced protein expression of pro-tumorigenic cytokines IL-6 and TNF-α in the colon after AOM/DSS treatment. Additionally, LMP7-deficient mice also exhibit significantly decreased mRNA levels of pro-tumorigenic chemokines CXCL1, CXCL2 and CXCL3, as well as cell adhesion molecule VCAM-1, thus highlighting the role of LMP7 in regulation of these pro-tumorigenic factors. The net result of the lack of pro-tumorigenic cytokines and chemokines is an impaired recruitment and subsequent activity of tumour-associated neutrophils (TANs) in the colonic lamina propria. Furthermore, we show that the absence or pharmacological inhibition of LMP7 and the consequent blockade of NF-κB, abrogated the production IL-17A, which possesses a potent carcinogenic activity in the gut.
Moreover, in vivo administration of a selective LMP7 inhibitor „ONX-0914‟ during CAC induction reduced the tumour incidence in wild-type (WT) mice. Taken together, we identify the iP complex as a crucial mediator of inflammation-driven colon carcinogenesis and we also propose LMP7 as a potential therapeutic target for CAC to limit the ongoing tumorigenesis in inflammatory bowel disease (IBD) patients. |
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| দৈহিক বর্ননা: | 118 Seiten |
| ডিওআই: | 10.17192/z2016.0895 |