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.

Helicobacter, Inflammation, and Gastric Cancer

“…COX2 also enhances cell growth and angiogenesis, ROS modify protein function, IL6 activates STAT3 further enhancing cell growth and stimulating growth factor production including the Reg protein 28,29,30 . TNF-alpha and IL6 appear to create a positive feedback loop during cancer development, and also activate ERK/ MAPK cascades known to regulate cell proliferation, migration and angiogenesis 31 . In addition, IL1-beta, TNF-alpha and IL-6 activate c-Jun kinase (JNK) resulting in cell death induced compensatory proliferation 28, 32,33 .…”

Nardilysin controls intestinal tumorigenesis through HDAC1/p53–dependent transcriptional regulation

“…Although previous reports have shown that NRDC is highly expressed in cancer cells in breast, gastric, and esophageal cancer cells and promotes cell growth (15,21,22), its function during tumorigenesis has not been completely elucidated. Therefore, in this study, we aimed to elucidate the role of NRDC in intestinal tumorigenesis, and show that NRDC regulates intestinal tumor development through the HDAC1/p53 pathway.…”

“…For instance, forced expression of NRDC or administration of the NRDC protein enhances ectodomain shedding of TNF-α through the activation of a disintegrin and metalloproteinase 17 (ADAM17) (12). Importantly, the enhancement of TNF-α shedding by NRDC and the subsequent activation of TNF-R signaling are involved in the growth of gastric cancer cell lines (15).…”

Nardilysin inhibits pancreatitis and suppresses pancreatic ductal adenocarcinoma initiation in mice

“…In addition, NRDC is highly expressed in gastric, breast and oesophageal cancer cells27–29 and promotes cell growth in vitro 27. We previously showed that NRDC maintains intrinsic nuclear factor-kappa B (NF-κB) signalling, and consequently cancer growth, by enhancing ectodomain shedding of tumour necrosis factor-alpha (TNF-α) in gastric cancer cell lines 27.…”

“…We previously showed that NRDC maintains intrinsic nuclear factor-kappa B (NF-κB) signalling, and consequently cancer growth, by enhancing ectodomain shedding of tumour necrosis factor-alpha (TNF-α) in gastric cancer cell lines 27. We also recently demonstrated that NRDC is required for maintaining pancreatic β-cell function in mice 26.…”