癌变
偶氮甲烷
下调和上调
癌症研究
免疫系统
生物
前列腺素E2
前列腺素E
信号转导
受体
细胞生物学
免疫学
基因
内分泌学
生物化学
作者
Ce Tang,Hao Sun,Motohiko Kadoki,Wei Han,Xiaoqi Ye,Yulia Makusheva,Jianping Deng,Bo Feng,Ding Qiu,Ying Tan,Xinying Wang,Zehao Guo,Chanyan Huang,Sui Peng,Minhu Chen,Yoshiyuki Adachi,Naohito Ohno,Sergio Trombetta,Yoichiro Iwakura
标识
DOI:10.1038/s41467-023-37229-x
摘要
Abstract Dectin-1 (gene Clec7a ), a receptor for β-glucans, plays important roles in the host defense against fungi and immune homeostasis of the intestine. Although this molecule is also suggested to be involved in the regulation of tumorigenesis, the role in intestinal tumor development remains to be elucidated. In this study, we find that azoxymethane-dextran-sodium-sulfate-induced and Apc Min -induced intestinal tumorigenesis are suppressed in Clec7a −/− mice independently from commensal microbiota. Dectin-1 is preferentially expressed on myeloid-derived suppressor cells (MDSCs). In the Clec7a −/− mouse colon, the proportion of MDSCs and MDSC-derived prostaglandin E 2 (PGE 2 ) levels are reduced, while the expression of IL-22 binding protein (IL-22BP; gene Il22ra2 ) is upregulated. Dectin-1 signaling induces PGE 2 -synthesizing enzymes and PGE 2 suppresses Il22ra2 expression in vitro and in vivo. Administration of short chain β-glucan laminarin, an antagonist of Dectin-1, suppresses the development of mouse colorectal tumors. Furthermore, in patients with colorectal cancer (CRC), the expression of CLEC7A is also observed in MDSCs and correlated with the death rate and tumor severity. Dectin-1 signaling upregulates PGE 2 -synthesizing enzyme expression and PGE 2 suppresses IL22RA2 expression in human CRC-infiltrating cells. These observations indicate a role of the Dectin-1-PGE 2 -IL-22BP axis in regulating intestinal tumorigenesis, suggesting Dectin-1 as a potential target for CRC therapy.
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