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Receptor Activator of Nuclear Factor-B Ligand (RANKL) Expression in Hepatocellular Carcinoma With Bone Metastasis

¹ Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu 874-0838, Japan
² Department of Surgery I, Oita University Faculty of Medicine, 1-1 Hasama-machi, 879-5593, Oita, Japan

Correspondence: Address correspondence and reprint requests to: Masaki Mori, MD; E-mail: mmori{at}beppu.kyushu-u.ac.jp

Background: Although receptor activator of nuclear factor-B ligand (RANKL) seems to be involved in the development of bone metastases in several malignant tumors, its role in hepatocellular carcinoma (HCC) has not been investigated.

Methods: We retrospectively examined the immunohistochemical expression of RANKL in formalin-fixed, paraffin-embedded resected specimens obtained from 96 patients with HCC with (n = 16) and without (n = 80) bone metastases. In addition, tumor RANKL mRNA expression was evaluated by reverse transcriptase–polymerase chain reaction (RT-PCR) in five selected patients. We analyzed the relationship between RANKL expression level, bone metastasis development, and survival rate of patients with HCC after hepatic resection.

Results: Of the 96 patients with HCC, serum hepatitis C virus antibody was detected in 43.5% of patients and hepatitis B surface antigen in 29.5% of patients. Thirty-three patients (36.5%) also had liver cirrhosis. Immunohistochemical analysis showed that RANKL protein was present in 10 (62.5%) of 16 patients with HCC with bone metastasis compared with 21 (26.3%) of 80 patients with HCC without bone metastasis; we found that RANKL expression was statistically significantly correlated to bone metastasis development (P < .01). RANKL mRNA expression was confirmed by RT-PCR in patients positive for RANKL protein expression by immunohistochemistry. The 5-year cancer-related (P < .01) and disease-free survival (P < .01) rates after hepatic resection were statistically significantly worse in patients positive for RANKL expression compared with RANKL-negative patients.

Conclusions: Some HCC cells produced the crucial bone resorption regulator RANKL. Because RANKL modulates bone turnover, its presence would have profound implications for the establishment and development of bone metastases.

Key Words: Hepatocellular carcinoma • Receptor activator of nuclear factor-B ligand • Bone metastasis • Prognosis • Recurrence

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