Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
EMBO Mol Med. 2012 May;4(5):396-411. doi: 10.1002/emmm.201200216. Epub 2012 Feb 20.
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.
脑啡肽酶（NRDc）是 M16 家族的金属内肽酶，通过增强 ADAM 蛋白的蛋白酶活性，促进各种生长因子和细胞因子前体形式的胞外结构域脱落。在这里，我们展示了 NRDc 在胃癌细胞中的促生长作用。对临床样本的分析表明，胃癌患者的血清和癌上皮中 NRDc 蛋白表达经常升高。NRDc 敲低后，体外和异种移植实验均抑制肿瘤细胞生长。在胃癌细胞中，NRDc 促进肿瘤坏死因子-α（pro-TNF-α）的脱落，从而刺激 NF-κB 调节的多种细胞因子（如白细胞介素（IL）-6）的表达。反过来，IL-6 激活 STAT3，导致下游与生长相关的基因转录上调。代表性的 ADAM 蛋白酶 ADAM17 或 ADAM10 的基因沉默模拟了 NRDc 敲低诱导的细胞因子表达和细胞生长变化。我们的研究结果表明，胃癌细胞的生长是通过自主的 TNF-α-NF-κB 和 IL-6-STAT3 信号维持的，NRDc 和 ADAM 蛋白酶通过刺激 TNF-α 的胞外结构域脱落来启动这些信号级联反应。
