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

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Abstract

Background

Although receptor activator of nuclear factor-κB 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.

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Acknowledgments

Presented in part at The Society of Surgical Oncology 59th Annual Cancer Symposium, March 23–26, 2006, San Diego, CA. This work was supported in part by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (grant 16591329), Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, and Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (grants 17109013, 17591411, and 17591413). The authors thank MS. Yuko Nakagawa and Fusayo Kawamura for their technical assistance with the immunohistochemistry, and Yuichi Endo M.D. and MS. Kazue Ogata for assistance with the reverse transcriptase–polymerase chain reaction analysis.

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Authors and Affiliations

  1. Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu, 874-0838, Japan

    Atsushi Sasaki MD, Kenji Ishikawa MD, Naotsugu Haraguchi MD, Hiroshi Inoue MD & Masaki Mori MD

  2. Department of Surgery I, Oita University Faculty of Medicine, 1-1 Hasama-machi, 879-5593, Oita, Japan

    Atsushi Sasaki MD, Tetsuya Ishio MD, Kohei Shibata MD, Masayuki Ohta MD & Seigo Kitano MD

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  1. Atsushi Sasaki MD
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Correspondence to Masaki Mori MD.

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Sasaki, A., Ishikawa, K., Haraguchi, N. et al. Receptor Activator of Nuclear Factor-κB Ligand (RANKL) Expression in Hepatocellular Carcinoma With Bone Metastasis. Ann Surg Oncol 14, 1191–1199 (2007). https://doi.org/10.1245/s10434-006-9277-4

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