Abstract
RANK/RANKL plays a key role in metastasis of certain malignant tumors, which makes it a promising target for developing novel therapeutic strategies for cancer. However, the prognostic value and pro-metastatic activity of RANK in endometrial cancer (EC) remain to be determined. Thus, the present study investigated the effect of RANK on the prognosis of EC patients, as well as the pro-metastatic activity of EC cells. The results indicated that those with high expression of RANK showed decreased overall survival and progression-free survival. Statistical analysis revealed the positive correlations between RANK/RANKL expression and metastasis-related factors. Additionally, RANK/RANKL significantly promoted cell migration/invasion via activating AKT/β-catenin/Snail pathway in vitro. However, RANK/RANKL-induced AKT activation could be suppressed after osteoprotegerin (OPG) treatment. Furthermore, the combination of medroxyprogesterone acetate (MPA) and RANKL could in turn attenuate the effect of RANKL alone. Similarly, MPA could partially inhibit the RANK-induced metastasis in an orthotopic mouse model via suppressing AKT/β-catenin/Snail pathway. Therefore, therapeutic inhibition of MPA in RANK/RANKL-induced metastasis was mediated by AKT/β-catenin/Snail pathway both in vitro and in vivo, suggesting a potential target of RANK for gene-based therapy for EC.
Highlights
Endometrial cancer (EC) is the fourth most common cancer among women in the United States, with an estimated 54, 870 new cases and 10, 170 deaths in 2015 [1]
Metastasis is widely recognized as intricate, multistep processes and closely associated with worse prognosis in tumors
It must be mentioned that the poor prognosis of patients with endometrioid EC has been associated with the extra-pelvic spread of the tumor [25]
Summary
Endometrial cancer (EC) is the fourth most common cancer among women in the United States, with an estimated 54, 870 new cases and 10, 170 deaths in 2015 [1]. Metastasis, the leading cause of death in EC, is initiated by compact regulation of associated molecules. It depends on the balance between pro-metastatic and anti-metastatic factors [3, 4]. Receptor activator of NF-κB ligand (RANKL), the ligand of RANK, plays a pivotal, lineage-specific role in tumorigenesis and/or metastasis [8]. Evidences demonstrated that RANKL inhibition could contribute to a better clinical outcome [12]. Despite these encouraging data, the relationship between clinical outcome and tissuebased protein expression, especially RANK, is unclear
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