Nardilysin and ADAM proteases promote gastric cancer cell growth by activating intrinsic cytokine signalling via enhanced ectodomain shedding of TNF‐α

EMBO Molecular Medicine

Keitaro Kanda⁵  Hideyuki Komekado⁵  Tateo Sawabu⁵  Shoko Ishizu⁵  Yuki Nakanishi⁵  Masato Nakatsuji⁵  Reiko Akitake-Kawano⁵  Mikiko Ohno⁴  Yoshinori Hiraoka⁴  Mayumi Kawada⁵  Kenji Kawada²  Yoshiharu Sakai²  Kyoichi Matsumoto³  Makoto Kunichika¹  Takeshi Kimura⁴  Hiroshi Seno⁷  Eiichiro Nishi⁶ 

[1] Sanyo Chemical Industries Ltd., Kyoto, Japan;Department of Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan;Mikuri Immunology Laboratory Inc., Osaka, Japan;Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan;Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;E-mail address: E-mail address: 关键词: ADAM proteases;    gastric cancer;    IL‐6;    nardilysin;    NF‐κB;   

DOI  :  10.1002/emmm.201200216

来源: Wiley

【 摘 要 】

Abstract

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-α), which stimulates expression of NF-κB-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-α–NF-κB and IL-6–STAT3 signalling, and that NRDc and ADAM proteases turn on these signalling cascades by stimulating ectodomain shedding of TNF-α.

【 授权许可】

Unknown   
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