title: Nardilysin and ADAM proteases promote gastric cancer cell growth by activating intrinsic cytokine signalling via enhanced ectodomain shedding of TNF-α.
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.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Kanda
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Komekado
authors.forename: Tateo
authors.initials: T
authors.lastname: Sawabu
authors.forename: Shoko
authors.initials: S
authors.lastname: Ishizu
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakanishi
authors.forename: Masato
authors.initials: M
authors.lastname: Nakatsuji
authors.forename: Reiko
authors.initials: R
authors.lastname: Akitake-Kawano
authors.forename: Mikiko
authors.initials: M
authors.lastname: Ohno
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hiraoka
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kawada
authors.forename: Kenji
authors.initials: K
authors.lastname: Kawada
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Sakai
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Kunichika
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Seno
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Nishi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
mesh_terms: D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism*; D004847:Epithelial Cells / Q000201:enzymology* / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000473:pathology*
chemical_list: D016207:Cytokines; D008666:Metalloendopeptidases