期刊
EMBO MOLECULAR MEDICINE
卷 4, 期 5, 页码 396-411出版社
WILEY-BLACKWELL
DOI: 10.1002/emmm.201200216
关键词
ADAM proteases; gastric cancer; IL-6; nardilysin; NF-?B
资金
- Japan Society for Promotion of Science (JSPS) [21229009, 23300117, 23590937, 23659154, 23117519, 22790641]
- Ministry of Health, Labour and Welfare, Japan
- Research Foundation of Translational Research Center at Kyoto University Hospital
- Takeda Science Foundation
- Daiichi Sankyo
- Grants-in-Aid for Scientific Research [23300117, 21229009, 23122510, 10J02434, 23590937, 09J40033, 23659154, 24659363, 22790641, 23659755, 24590914] Funding Source: KAKEN
Nardilysin (NRDc), a metalloendopeptidase of the M16 family, promotes ectodomain shedding of the precursor forms of various growth factors and cytokines by enhancing the protease activities of ADAM proteins. Here, we show the growth-promoting role of NRDc in gastric cancer cells. Analyses of clinical samples demonstrated that NRDc protein expression was frequently elevated both in the serum and cancer epithelium of gastric cancer patients. After NRDc knockdown, tumour cell growth was suppressed both in vitro and in xenograft experiments. In gastric cancer cells, NRDc promotes shedding of pro-tumour necrosis factor-alpha (pro-TNF-a), which stimulates expression of NF-?B-regulated multiple cytokines such as interleukin (IL)-6. In turn, IL-6 activates STAT3, leading to transcriptional upregulation of downstream growth-related genes. Gene silencing of ADAM17 or ADAM10, representative ADAM proteases, phenocopied the changes in cytokine expression and cell growth induced by NRDc knockdown. Our results demonstrate that gastric cancer cell growth is maintained by autonomous TNF-aNF-?B and IL-6STAT3 signalling, and that NRDc and ADAM proteases turn on these signalling cascades by stimulating ectodomain shedding of TNF-a.
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