Receptor activator of nuclear factor-kappaB ligand (RANKL) expression in hepatocellular carcinoma with bone metastasis.
BACKGROUND
Although receptor activator of nuclear factor-kappaB 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.
Sasaki
Atsushi
A
Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu, 874-0838, Japan.
Ishikawa
Kenji
K
Haraguchi
Naotsugu
N
Inoue
Hiroshi
H
Ishio
Tetsuya
T
Shibata
Kohei
K
Ohta
Masayuki
M
Kitano
Seigo
S
Mori
Masaki
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006514:Hepatitis B Surface Antigens / Q000097:blood; D018937:Hepatitis C Antibodies / Q000097:blood; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D053245:RANK Ligand / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D006514:Hepatitis B Surface Antigens; D018937:Hepatitis C Antibodies; D053245:RANK Ligand; D012333:RNA, Messenger; C505688:TNFSF11 protein, human