title: Nardilysin promotes hepatocellular carcinoma through activation of signal transducer and activator of transcription 3.
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.
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kasai
authors.affiliation: 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.
authors.forename: Kan
authors.initials: K
authors.lastname: Toriguchi
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Etsuro
authors.initials: E
authors.lastname: Hatano
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Nishi
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Ohno
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Yoh
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Fukuyama
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nishio
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Okuno
authors.affiliation: Department of Target Therapy and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Iwaisako
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Seo
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Taura
authors.affiliation: Sanyo Chemical Industries, Kyoto, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kurokawa
authors.affiliation: Sanyo Chemical Industries, Kyoto, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kunichika
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Pharmacology, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Eiichiro
authors.identifier: http://orcid.org/0000-0002-8188-8026
authors.initials: E
authors.lastname: Nishi
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011379:Prognosis; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D008666:Metalloendopeptidases; C087976:nardilysin
keywords: Hepatocellular carcinoma; nardilysin; prognostic marker; signal transducer and activator of transcription 3; spheroid