期刊
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
卷 108, 期 4, 页码 -出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/djv364
关键词
-
类别
资金
- National Natural Science Foundation of China [81072442, 81471588]
- Ministry of Science and Technology of China [2012AA021010]
- Ministry of Health [201302009]
Background: The TLR/MyD88 signaling pathway is an important driver of inflammation and cancer and is a possible target for antitumor therapy. Methods: We generated a MyD88 inhibitor (TJ-M2010-5), which was designed to bind to the TIR domain of MyD88 to interfere with its homodimerization, and the TLR/MyD88 signal pathway. We utilized a mouse model of azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colitis-associated cancer (CAC) in combination with TJ-M2010-5 administration to investigate the anti-inflammation-related cancer effect of MyD88 inhibitor in vivo. Data were analyzed with one-way and repeated measures analysis of variance. Differences in survival between groups were compared using the log rank test. All statistical tests were two-sided. Results: TJ-M2010-5 inhibited MyD88 homodimerization in transfected HEK293 cells in a concentration-dependent manner and suppressed MyD88 signaling in LPS-responsive RAW 264.7 cells in vitro. In a 10-week CAC mouse model (n = 30 per group), TJ-M2010-5 treatment statistically significantly reduced AOM/DSS-induced colitis and completely prevented CAC development with less related body mass loss, resulted in 0% mortality of treated mice (compared with 53% mortality of control mice), decreased cell proliferation, and increased apoptosis in colon tissue. TJ-M2010-5 treatment also inhibited production of inflammatory cytokines and chemokines (TNF-alpha, IL-6, G-CSF, MIP-1 beta, TGF-beta 1, IL-11, IL-17A, IL-22 and IL-23) and infiltration of immune cells (macrophages, dendritic cells, neutropihls and CD(+)4 T cells) in colon tissues of mice. Conclusions: Our findings suggest that TLR/MyD88 signaling may be a therapeutic target for CAC intervention and MyD88 inhibitors may be a promising therapeutic modality for treating patients with colitis or CAC.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据