title: Receptor activator of NF-kappaB Ligand (RANKL) expression is associated with epithelial to mesenchymal transition in human prostate cancer cells.
abstract: Epithelial-mesenchymal transition (EMT) in cancer describes the phenotypic and behavioral changes of cancer cells from indolent to virulent forms with increased migratory, invasive and metastatic potential. EMT can be induced by soluble proteins like transforming growth factor beta1 (TGFbeta1) and transcription factors including Snail and Slug. We utilized the ARCaP(E)/ARCaP(M) prostate cancer progression model and LNCaP clones stably overexpressing Snail to identify novel markers associated with EMT. Compared to ARCaP(E) cells, the highly tumorigenic mesenchymal ARCaP(M) and ARCaP(M1) variant cells displayed a higher incidence of bone metastasis after intracardiac administration in SCID mice. ARCaP(M) and ARCaP(M1) expressed mesenchymal stromal markers of vimentin and N-cadherin in addition to elevated levels of Receptor Activator of NF-kappaB Ligand (RANKL). We observed that both epidermal growth factor (EGF) plus TGFbeta1 treatment and Snail overexpression induced EMT in ARCaP(E) and LNCaP cells, and EMT was associated with increased expression of RANKL protein. Finally, we determined that the RANKL protein was functionally active, promoting osteoclastogenesis in vitro. Our results indicate that RANKL is a novel marker for EMT during prostate cancer progression. RANKL may function as a link between EMT, bone turnover, and prostate cancer skeletal metastasis.
authors.affiliation: Molecular Urology and Therapeutics Program, Department of Urology and Winship Cancer Institute, Emory University School of Medicine, 1365B Clifton Road, NE, Atlanta, GA 30322, USA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Odero-Marah
authors.forename: Ruoxiang
authors.initials: R
authors.lastname: Wang
authors.forename: Gina
authors.initials: G
authors.lastname: Chu
authors.forename: Majd
authors.initials: M
authors.lastname: Zayzafoon
authors.forename: Jianchun
authors.initials: J
authors.lastname: Xu
authors.forename: Chunmeng
authors.initials: C
authors.lastname: Shi
authors.forename: Fray F
authors.initials: FF
authors.lastname: Marshall
authors.forename: Haiyen E
authors.initials: HE
authors.lastname: Zhau
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D016723:Bone Remodeling / Q000187:drug effects / Q000235:genetics; D015820:Cadherins / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054337:Cell Dedifferentiation / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000235:genetics / Q000276:immunology; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000276:immunology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014746:Vimentin / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D053245:RANK Ligand; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; C505688:TNFSF11 protein, human; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D014746:Vimentin; D004815:Epidermal Growth Factor