Kasai Yosuke, Toriguchi Kan, Hatano Etsuro, Nishi Kiyoto, Ohno Mikiko, Yoh Tomoaki, Fukuyama Keita, Nishio Takahiro, Okuno Masayuki, Iwaisako Keiko, Seo Satoru, Taura Kojiro, Kurokawa Masato, Kunichika Makoto, Uemoto Shinji, Nishi Eiichiro
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA.
Cancer Sci. 2017 May;108(5):910-917. doi: 10.1111/cas.13204. Epub 2017 Apr 24.
Nardilysin (NRDC) is a metalloendopeptidase of the M16 family. We previously showed that NRDC activates inflammatory cytokine signaling, including interleukin-6-signal transducer and activator of transcription 3 (STAT3) signaling. NRDC has been implicated in the promotion of breast, gastric and esophageal cancer, as well as the development of liver fibrosis. In this study, we investigated the role of NRDC in the promotion of hepatocellular carcinoma (HCC), both clinically and experimentally. We found that NRDC expression was upregulated threefold in HCC tissue compared to the adjacent non-tumor liver tissue, which was confirmed by immunohistochemistry and western blotting. We also found that high serum NRDC was associated with large tumor size (>3 cm, P = 0.016) and poor prognosis after hepatectomy (median survival time 32.0 vs 73.9 months, P = 0.003) in patients with hepatitis C (n = 120). Diethylnitrosamine-induced hepatocarcinogenesis was suppressed in heterozygous NRDC-deficient mice compared to their wild-type littermates. Gene silencing of NRDC with miRNA diminished the growth of Huh-7 and Hep3B spheroids in vitro. Notably, phosphorylation of STAT3 was decreased in NRDC-depleted Huh-7 spheroids compared to control spheroids. The effect of a STAT3 inhibitor (S3I-201) on the growth of Huh-7 spheroids was reduced in NRDC-depleted cells relative to controls. Our results show that NRDC is a promising prognostic marker for HCC in patients with hepatitis C, and that NRDC promotes tumor growth through activation of STAT3.
纳地溶素（NRDC）是M16家族的一种金属内肽酶。我们之前表明，NRDC可激活炎症细胞因子信号传导，包括白细胞介素-6-信号转导和转录激活因子3（STAT3）信号传导。NRDC与乳腺癌、胃癌和食管癌的进展以及肝纤维化的发展有关。在本研究中，我们从临床和实验两方面研究了NRDC在肝细胞癌（HCC）进展中的作用。我们发现，与相邻的非肿瘤肝组织相比，HCC组织中NRDC的表达上调了三倍，这通过免疫组织化学和蛋白质印迹法得到了证实。我们还发现，在丙型肝炎患者（n = 120）中，高血清NRDC与肿瘤体积较大（>3 cm，P = 0.016）以及肝切除术后预后不良（中位生存时间32.0对73.9个月，P = 0.003）相关。与野生型同窝小鼠相比，杂合NRDC缺陷小鼠中由二乙基亚硝胺诱导的肝癌发生受到抑制。用miRNA对NRDC进行基因沉默可在体外减少Huh-7和Hep3B球体的生长。值得注意的是，与对照球体相比，NRDC缺失的Huh-7球体中STAT3的磷酸化水平降低。相对于对照，在NRDC缺失的细胞中，STAT3抑制剂（S3I-201）对Huh-7球体生长的作用减弱。我们的结果表明，NRDC是丙型肝炎患者HCC的一个有前景的预后标志物，并且NRDC通过激活STAT3促进肿瘤生长。
