Differential Expression of the RANKL/RANK/OPG System Is Associated with Bone Metastasis in Human Non-Small Cell Lung Cancer

Abstract

BackgroundHuman non-small cell lung cancer (NSCLC) patients exhibit a high propensity to develop skeletal metastasis, resulting in excessive osteolytic activity. The RANKL/RANK/OPG system, which plays a pivotal role in bone remodeling by regulating osteoclast formation and activity, is of potential interest in this context.Materials and MethodsReverse transcriptase polymerase chain reaction, western blotting, and immunohistochemical analysis were used to examine the expression of RANKL, RANK, and OPG in human NSCLC cell lines with different metastatic potentials, as well as in 52 primary NSCLC samples and 75 NSCLC bone metastasis samples. In primary NSCLC patients, the expression of these proteins was correlated with clinicopathological parameters. Recombinant human RANKL and transfected RANKL cDNA were added to the PAa cell line to evaluate the promoter action of RANKL during the process of metastasis in vitro and in vivo.ResultsUp-regulated RANKL, RANK, and OPG expression and increased RANKL:OPG ratio were detected in NSCLC cell lines and in tumor tissues with bone metastasis, and were correlated with higher metastatic potential. The metastatic potential of NSCLC in vitro and in vivo, including migration and invasion ability, was significantly enhanced by recombinant human RANKL and the transfection of RANKL cDNA, and was impaired after OPG was added. The increased expression of RANKL and OPG correlated with tumor stage, lymph node metastasis, and distant metastasis.ConclusionsDifferential expression of RANKL, RANK, and OPG is associated with the metastatic potential of human NSCLC to skeleton, raising the possibility that the RANKL/RANK/OPG system could be a therapeutic target for the treatment of metastatic NSCLC patients.

RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs

“…Higher RANKL and OPG expression were observed in more advanced metastatic tumours (Po0.05). Higher RANKL expression was found in poorly differentiated tumours (Peng et al, 2013). A summary of these findings is reported in Table 5.…”

Upregulation of osteoprotegerin expression correlates with bone invasion and predicts poor clinical outcome in oral cancer

“…The prognostic significance of OPG has already been demonstrated in a variety of malignancies, including non-small cell lung cancer (NSCLC), gastric, colorectal, and bladder urothelial cancers [8][9][10][11]. In a recent study of NSCLC, high OPG expression was significantly associated with adverse clinical features, such as advanced tumor stage and lymph node involvement [9].…”

“…There are multiple lines of evidence indicating that abnormal expression of the RANKL/RANK/OPG molecular triad mediates tumor progression and metastasis in a wide range of malignancies, including breast, prostate, colorectal, lung, bladder and gastric cancers [6][7][8][9][10][11]. It has been demonstrated that the RANKL/RANK/ OPG system plays a critical role in the crosstalk between cancer cells and the bone microenvironment, promoting a vicious cycle between bone resorption and tumor growth in bone [12].…”

Serum osteoprotegerin and future risk of cancer and cancer-related mortality in the general population: the Tromsø study

“…No associations were observed between serum OPG and risk of cancer and cancer-related mortality in the 13 respiratory system. In human non-small cell lung cancer (NSCLC) tissue samples, significantly stronger immunostaining for OPG, RANKL and RANK were observed in bone metastases than in tumor cells at the primary site (29). Furthermore, the RANKL:OPG ratios were significantly higher in bone metastases compared with primary NSCLC tissue samples (29).…”