Aberrant expression of melanoma-associated antigen-D2 serves as a prognostic indicator of hepatocellular carcinoma outcome following curative hepatectomy.

Ryoji Hashimoto,Yasuhiro Kodera,Mitsuro Kanda,Soki Hibino,Goro Nakayama,Shuji Nomoto,Suguru Yamada,Hideki Takami,Hisaharu Oya,Dai Shimizu,Hiroyuki Sugimoto,Michitaka Fujiwara,Tsutomu Fujii,Masahiko Koike,Yukiyasu Okamura

doi:10.3892/ol.2014.2823

Abstract

Hepatocellular carcinoma (HCC) is the most common cause of cancer-related mortality globally. Since the prognosis of advanced HCC patients is extremely poor, the development of novel molecular targets for diagnosis and therapy is urgently required. In the present study, the expression of the melanoma-associated antigen-D2 (MAGE-D2) gene was investigated to determine whether it affects the malignant phenotype of HCC and thus, may serve as a marker of prognosis. Therefore, the expression of MAGE-D2 mRNA and MAGE-D2 protein in nine HCC cell lines and 151 pairs of surgical tissues was analyzed. mRNA expression levels were analyzed using reverse transcription-quantitative polymerase chain reaction and immunohistochemistry was used to compare the clinicopathological parameters of the tumors. A significant difference in the level of MAGE-D2 expression was observed between the normal liver and chronic hepatitis tissues, however, no significant differences were identified among the levels of the chronic hepatitis, cirrhosis and HCC tissues. The expression patterns of the MAGE-D2 protein were consistent with those of its mRNA. The expression levels of MAGE-D2 mRNA in 66 of 151 (44%) patients were higher in the HCC tissues compared with the corresponding non-cancerous tissues. In addition, the disease-specific survival time was significantly shorter for patients with higher levels of MAGE-D2 mRNA expression. Multivariate analysis identified increased expression of MAGE-D2 mRNA as an independent prognostic factor for disease-specific survival (hazard ratio, 2.65; 95% confidence interval, 1.43–4.98; P=0.002). However, increased expression levels of MAGE-D2 mRNA were not significantly associated with other clinicopathological parameters, including extrahepatic recurrence. These results indicated that MAGE-D2 mRNA affects tumor progression and may serve as a prognostic indicator following curative resection. In addition, MAGE-D2 may provide a target for the therapy of HCC.

Highlights

Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and the third leading cause of cancer‐related mortality worldwide [1]
The melanoma‐associated antigen‐D2 (MAGE‐D2) mRNA expression levels were compared in the non‐cancerous tissues categorized by the background liver status as follows: Normal liver (n=10), chronic hepatitis (n=87), cirrhosis (n=54) and HCC tissues
A significant difference was observed between normal liver and chronic hepatitis tissues (P=0.037), whereas chronic hepatitis and cirrhosis were comparable, indicating that Melanoma‐associated antigens (MAGEs)‐D2 expression was stimulated by chronic inflammation, but not fibrosis (Fig. 1B)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and the third leading cause of cancer‐related mortality worldwide [1]. The incidence of HCC has rapidly increased and the disease has received considerable attention. Patients diagnosed with HCC often exhibit an adverse outcome due to the aggressive nature of the disease, and surgical resection is usually only effective at the early stages of the disease [2]. ~70% of these patients develop recurrent tumors within five years [3,4]. Even with the advent of the multikinase inhibitor, sorafenib, prolonged survival is limited [5,6]. The development of novel molecular targets for the diagnosis and therapy of HCC are urgently required

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Conclusion