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P040 USP16 regulates p65 activation in macrophages and promotes the inflammatory-carcinoma transformation process in IBD patients

Zhang, Y.(1);Wang, C.(1);Yao, L.(1);Li, M.(1);Jin, J.(2);Cao, Q.(1);

(1)Sir Run Run Shaw Hospital,Zhejiang University School of Medicine, Department of Gastroenterology, Hangzhou, China;(2)MOE Laboratory, Biosystem Homeostasis and Protection- and Life Sciences Institute-, Hangzhou, China

Background

Long duration colonic inflammation increases the risk in developing intestinal dysplasia and further tumorigenesis, which is known as colitis-associated cancer (CAC). USP16, a deubiquitinase, is reported to regulate the T cell and macrophage function in acute colitis. But its function in CAC is never been studied.

Methods

We analyzed USP16 expression in tumor tissues and para-tumor tissues from patients with CAC by immunofluorescent staining. Then we established a CAC model in USP16MKO (conditional knock out in macrophage cells) and wild type mice by azoxymethane (AOM) and dextran sodium sulfate (DSS). Associated inflammatory cytokines were examined in normal colon and CAC by real-time polymerase chain reaction. And the signaling pathways and molecular mechanisms were studied.

Results

Expression of USP16 was found to be increased in tumor tissues from CAC patients  than that in para-tumor controls. USP16MKO mice had fewer and smaller colon tumors than their WT littermates. Various inflammatory cytokines, including TnfIl12aIL12bIl23a and Il1b, were decreased in the colon tissues of USP16MKO mice. USP16 deficiency leads to the decrease of p65 activation and nucleation in macrophage. Through co-IP and immunofluorescent staining, USP16 was found to have an interaction with p65. And p65 deubiquitination was decreased in USP16 deficient macrophages.

Conclusion

USP16 is increased in colitis-associated cancer and regulates intestinal epithelial carcinogenesis by modulating pro-inflammatory responses in macrophages. USP16 serves as a deubiquitinase of P65 and thus promoting the activation and nucleation. Therefore, USP16 may serve as a novel therapeutic target to block inflammatory-cancer transformation 

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