title: Increased RANKL expression is related to tumour migration and metastasis of renal cell carcinomas.
abstract: Receptor activator of NF-kappaB ligand (RANKL) and its receptor, receptor activator of NF-kappaB (RANK), play a key role in osteoclastogenesis, and osteoprotegerin (OPG) acts as a decoy receptor for RANKL. We investigated the role of the RANKL-RANK-OPG system in renal cell carcinomas (RCCs), which frequently metastasize to bones. Real-time quantitative PCR revealed that RANKL mRNA expression was higher in clear cell RCCs than in papillary and chromophobe RCCs. Similarly, RANKL protein expression level in clear cell RCCs was higher than that in papillary and chromophobe RCCs, showing positive correlations with the primary tumour stage and distant metastasis. There was no significant association between the expression level of RANK, OPG and histological subtypes of RCC. RANKL and RANK expression was observed in metastatic RCCs in the bone and other organs, suggesting that they play a role in metastasis to the bone and other organs. Recombinant RANKL protein stimulated migration of a clear cell RCC cell line, Caki-1, in vitro, and this enhanced migration was inhibited by the administration of recombinant OPG protein. Furthermore, multivariate Cox analysis revealed that elevated RANKL and RANK expression with low-OPG expression was a significant and independent predictor of recurrence, bone metastasis and a poor prognosis. These data suggest that the RANKL-RANK-OPG system is involved not only in the bone metastasis of RCCs but also in metastasis to other organs through the stimulation of cancer cell migration.
authors.affiliation: Division of Diagnostic Pathology, Keio University Hospital, Tokyo, Japan. mikami-s@sc.itc.keio.ac.jp
authors.forename: Shuji
authors.initials: S
authors.lastname: Mikami
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Katsube
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Oya
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishida
authors.forename: Takeo
authors.initials: T
authors.lastname: Kosaka
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Mizuno
authors.forename: Satsuki
authors.initials: S
authors.lastname: Mochizuki
authors.forename: Tohru
authors.initials: T
authors.lastname: Ikeda
authors.forename: Makio
authors.initials: M
authors.lastname: Mukai
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
mesh_terms: D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D053244:Osteoprotegerin / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D053245:RANK Ligand / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B