Open AccessNardilysin and ADAM proteases promote gastric cancer cell growth by activating intrinsic cytokine signalling via enhanced ectodomain shedding of TNF‐α
Author(s) -
Kanda Keitaro,
Komekado Hideyuki,
Sawabu Tateo,
Ishizu Shoko,
Nakanishi Yuki,
Nakatsuji Masato,
AkitakeKawano Reiko,
Ohno Mikiko,
Hiraoka Yoshinori,
Kawada Mayumi,
Kawada Kenji,
Sakai Yoshiharu,
Matsumoto Kyoichi,
Kunichika Makoto,
Kimura Takeshi,
Seno Hiroshi,
Nishi Eiichiro,
Chiba Tsutomu
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201200216
Subject(s) - ectodomain , adam10 , proteases , tumor necrosis factor alpha , cytokine , cancer cell , gene knockdown , cancer , cell growth , cancer research , biology , microbiology and biotechnology , gene silencing , cell , apoptosis , immunology , disintegrin , metalloproteinase , biochemistry , matrix metalloproteinase , gene , enzyme , receptor , genetics
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.