NRAGE promotes the malignant phenotype of hepatocellular carcinoma

Shimizu,Dai; Kanda,Mitsuro; Sugimoto,Hiroyuki; Sueoka,Satoshi; Takami,Hideki; Ezaka,Kazuhiro; Tanaka,Yuri; Hashimoto,Ryoji; Okamura,Yukiyasu; Iwata,Naoki; Tanaka,Chie; Yamada,Suguru; Fujii,Tsutomu; Nakayama,Goro; Koike,Masahiko; Nomoto,Shuji; Fujiwara,Michitaka; Kodera,Yasuhiro

doi:10.3892/ol.2016.4120

NRAGE promotes the malignant phenotype of hepatocellular carcinoma

Authors:
- Dai Shimizu
- Mitsuro Kanda
- Hiroyuki Sugimoto
- Satoshi Sueoka
- Hideki Takami
- Kazuhiro Ezaka
- Yuri Tanaka
- Ryoji Hashimoto
- Yukiyasu Okamura
- Naoki Iwata
- Chie Tanaka
- Suguru Yamada
- Tsutomu Fujii
- Goro Nakayama
- Masahiko Koike
- Shuji Nomoto
- Michitaka Fujiwara
- Yasuhiro Kodera
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Affiliations: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466‑8550, Japan, Department of Hepatobiliary‑Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka 411‑8777, Japan, Department of Surgery, Aichi‑Gakuin University School of Dentistry, Nagoya, Aichi 464‑8651, Japan
Published online on: January 15, 2016 https://doi.org/10.3892/ol.2016.4120
Pages: 1847-1854

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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 of NRAGE in HCC is currently unknown, therefore, the present study aimed to identify the underlying function of NRAGE in 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 of NRAGE mRNA 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, increased NRAGE expression 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 increased NRAGE expression affects HCC progression via its interaction with AATF, and may represent a novel biomarker and molecular target for the treatment of HCC.

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