Nardilysin promotes hepatocellular carcinoma through activation of signal transducer and activator of transcription 3. Issue 5 (24th April 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Cancer science. Volume 108:Issue 5(2017)
• Page Start: 910
• Page End: 917
• Publication Date: 2017-04-24
• Subjects: Hepatocellular carcinoma -- nardilysin -- prognostic marker -- signal transducer and activator of transcription 3 -- spheroid; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.13204
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract : 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. Abstract : We investigated the role of nardilysin (NRDC) in the promotion of HCC, and showed that (i) NRDC is up‐regulated in HCC tissue; (ii) high serum NRDC is associated with increased tumor size and poor prognosis among patients with hepatitis C; (iii) diethylnitrosamine‐induced hepatocarcinogenesis is suppressed in NRDC‐deficient mice; and (iv) NRDC promotes the growth of HCC spheroids via activation of STAT3. These results indicate that NRDC is a promising prognostic marker for HCC in patients with hepatitis C, and that NRDC could be a therapeutic target for HCC.