Receptor for hyaluronic acid- mediated motility (RHAMM) regulates HT1080 fibrosarcoma cell proliferation via a β-catenin/c-myc signaling axis

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. beta-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 beta-catenin deficiency (p <= 0.01). beta-Catenin cytoplasmatic deposition is positively regulated by RHAMM (p <= 0.01). lmmunoflourescence and immunoprecipitation suggest that RHAMM/beta-catenin form an intracellular complex. Transfection experiments identified c-myc as candidate downstream mediator of RHAMM/beta-catenin effects on HT1080 fibrosarcoma cell proliferation. Conclusions: LMWHA/RHAMM downstream signaling regulates fibrosarcoma cell growth in a beta-catenin/c-myc dependent manner. General significance: The present study suggests that RHAMM is a novel beta-catenin intracellular binding partner, protecting beta-catenin from degradation and supporting the nuclear translocation of this key cellular mediator, which results in c-myc activation and enhanced fibrosarcoma cell growth. (C) 2016 Elsevier B.V. All rights reserved.