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10.1245/s10434-007-9698-8
Annals of Surgical Oncology 15:923-933 (2008)
© 2008 Society of Surgical Oncology
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Original Article

A Novel Function of the Receptor for Advanced Glycation End-Products (RAGE) in Association with Tumorigenesis and Tumor Differentiation of HCC

Kiyokazu Hiwatashi, MD1, Shinichi Ueno, MD, PhD1, Kazuhiro Abeyama, MD, PhD2, Fumitake Kubo, MD, PhD1, Masahiko Sakoda, MD, PhD1, Ikuro Maruyama, MD, PhD3, Masahiro Hamanoue, MD, PhD4, Shoji Natsugoe, MD, PhD1 and Takashi Aikou, MD, PhD1

1 Departments of Surgical Oncology and Digestive Surgery, Field of Oncology, Kagoshima University Graduate School of Medicine and Dental Sciences, Kagoshima, 890-8520, Japan
2 Preventive Medicine funded by Shin-Nippon Biomedical Laboratories Ltd. (SNBL), Kagoshima University Graduate School of Medicine and Dental Sciences, Kagoshima, 890-8520, Japan
3 Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medicine and Dental Sciences, Kagoshima, 890-8520, Japan
4 JA Kagoshima Kouseiren Hospital, Kagoshima, Japan

Correspondence: Address correspondence and reprint requests to: Shinichi Ueno; E-mail: ueno1{at}m.kufm.kagoshima-u.ac.jp

Background: The expression of the receptor for advanced glycation end products (RAGE) has an impact on the mechanisms giving rise to characteristic features of various cancer cells. The purpose of this study was to elucidate the clinicopathological relevance of the level of RAGE expression in patients with hepatocellular carcinoma (HCC) and to explore the effect of RAGE expression on the characteristic features of HCC.

Methods: The expression of RAGE was assessed in paired cancer and noncancerous tissues with HCC, using reverse-transcription polymerase chain reaction (RT-PCR), and immunohistochemistry. The quantitative RT-PCR data were analyzed in association with the clinicopathological factors of the patients with HCC. In in vitro experiments, the survival of RAGE-transfected Cos7 and mock-transfected Cos7 cells was compared under hypoxic conditions. In addition, after reducing RAGE levels in RAGE-transfected Cos7 cells by siRNA, similar experiments were performed.

Results: The expression of RAGE mRNA was lower in normal liver than in hepatitis and highest in HCC. Furthermore, in HCC, it was high in well- and moderately differentiated tumors but declined as tumors dedifferentiated to poorly differentiated HCC. Furthermore, HCC lines resistant to hypoxia were found to have higher levels of RAGE expression, and RAGE transfectant also showed significantly prolonged survival under hypoxia.

Conclusions: Our results suggest that HCC during the early stage of tumorigenesis with less blood supply may acquire resistance to stringent hypoxic milieu by hypoxia-induced RAGE expression.

Key Words: Hepatocellular carcinoma (HCC) • Receptor for advanced glycation end-products (RAGE) • Hypoxia-Reverse-transcription polymerase chain reaction (RT-PCR) • Immunohistochemistry






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