title: Receptor for hyaluronic acid- mediated motility (RHAMM) regulates HT1080 fibrosarcoma cell proliferation via a β-catenin/c-myc signaling axis.
abstract: BACKGROUND
  High levels of hyaluronan (HA) synthesis in various cancer tissues, including sarcomas, are correlated with tumorigenesis and malignant transformation. RHAMM (receptor for hyaluronic acid-mediated motility) is overexpressed during tumor development in different malignancies. β-Catenin is a crucial downstream mediator of the Wnt signaling cascade which facilitates carcinogenic events characterized by deregulated cell proliferation.
  
  
  METHODS
  Real-time PCR, in vitro cell proliferation assay, siRNA transfection, flow cytometry, immunoprecipitation, western blotting and immunofluorescence were utilized.
  
  
  RESULTS
  The reduction of RHAMM expression was strongly correlated with an inhibition of HT1080 fibrosarcoma cell growth (p≤0.01). LMWHA, in a RHAMM-dependent manner increases cell growth of HT1080 cells (p≤0.01). Both basal and LMWHA dependent growth of HT1080 cells was attenuated by β-catenin deficiency (p≤0.01). β-Catenin cytoplasmatic deposition is positively regulated by RHAMM (p≤0.01). Immunoflourescence and immunoprecipitation suggest that RHAMM/β-catenin form an intracellular complex. Transfection experiments identified c-myc as candidate downstream mediator of RHAMM/β-catenin effects on HT1080 fibrosarcoma cell proliferation.
  
  
  CONCLUSIONS
  LMWHA/RHAMM downstream signaling regulates fibrosarcoma cell growth in a β-catenin/c-myc dependent manner.
  
  
  CONCLUSIONS
  The present study suggests that RHAMM is a novel β-catenin intracellular binding partner, protecting β-catenin from degradation and supporting the nuclear translocation of this key cellular mediator, which results in c-myc activation and enhanced fibrosarcoma cell growth.
authors.affiliation: School of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Katerina
authors.initials: K
authors.lastname: Kouvidi
authors.affiliation: School of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Berdiaki
authors.affiliation: School of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Tzardi
authors.affiliation: Department of Surgery and Morphology, University of Insubria, Varese, Italy.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Karousou
authors.affiliation: Department of Surgery and Morphology, University of Insubria, Varese, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Passi
authors.affiliation: School of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Dragana
authors.initials: D
authors.lastname: Nikitovic
authors.affiliation: School of Medicine, University of Crete, Heraklion, Greece. Electronic address: tzanakak@med.uoc.gr.
authors.forename: George N
authors.initials: GN
authors.lastname: Tzanakakis
mesh_terms: D021581:Active Transport, Cell Nucleus; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000235:genetics; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis* / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin; C098946:hyaluronan-mediated motility receptor
keywords: ERK1/2; Fibrosarcoma cell proliferation; LMWHA; RHAMM; β-Catenin