title: NRAGE promotes the malignant phenotype of hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is a fatal disease, primarily due to the limited effective therapies available for patients with advanced or recurrent stages of the disease. Therefore, in order to improve patient prognosis, it is important to identify an informative biomarker for HCC progression, as well as a molecular target for therapy. Neurotrophin receptor-interacting melanoma antigen-encoding protein (NRAGE), a member of the type II melanoma-associated antigen family, mediates apoptosis and cell death through interactions with a wide range of proteins, and is implicated as a tumor suppressor or oncoprotein depending on cell type. However, the role ofNRAGEin HCC is currently unknown, therefore, the present study aimed to identify the underlying function ofNRAGEin HCC tumorigenesis. Resected tumor and non-cancerous liver tissues from 151 patients with HCC, alongside HCC cell lines, were analyzed by polymerase chain reaction and immunohistochemical techniques to determine NRAGE expression levels, as well as the expression levels of potential genes encoding interacting proteins. It was demonstrated that the expression levels ofNRAGEmRNA correlated significantly with those of apoptosis-antagonizing transcription factor (AATF), and were not affected by cirrhosis in non-cancerous liver tissues when compared to elevated levels in HCC tissues. The expression patterns of NRAGE protein and mRNA were consistent among 30 representative specimen pairs. Furthermore, increasedNRAGEexpression in patients with HCC correlated significantly with a shorter disease-specific survival time, and was identified as an independent prognostic factor via multivariate analysis (hazard ratio, 2.23; 95% confidence interval, 1.06-3.83; P=0.020). Therefore, the results of the present study indicated that increasedNRAGEexpression affects HCC progression via its interaction withAATF, and may represent a novel biomarker and molecular target for the treatment of HCC.
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Shimizu
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Mitsuro
authors.initials: M
authors.lastname: Kanda
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugimoto
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sueoka
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Takami
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ezaka
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Department of Hepatobiliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka 411-8777, Japan.
authors.forename: Yukiyasu
authors.initials: Y
authors.lastname: Okamura
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Goro
authors.initials: G
authors.lastname: Nakayama
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Koike
authors.affiliation: Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi 464-8651, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Nomoto
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Michitaka
authors.initials: M
authors.lastname: Fujiwara
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kodera
keywords: apoptosis-antagonizing transcription factor; expression; hepatocellular carcinoma; neurotrophin receptor-interacting melanoma antigen-encoding protein; progression