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. GENERAL SIGNIFICANCE: 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.
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. GENERAL SIGNIFICANCE: 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: Shuai Ye; Ying Liu; Ashley M Fuller; Rohan Katti; Gabrielle E Ciotti; Susan Chor; Md Zahidul Alam; Samir Devalaraja; Kristin Lorent; Kristy Weber; Malay Haldar; Michael A Pack; T S Karin Eisinger-Mathason Journal: Mol Cancer Res Date: 2020-01-27 Impact factor: 5.852
Authors: Cornelia Tolg; Muhan Liu; Katelyn Cousteils; Patrick Telmer; Khandakar Alam; Jenny Ma; Leslie Mendina; James B McCarthy; Vincent L Morris; Eva A Turley Journal: J Biol Chem Date: 2020-03-12 Impact factor: 5.157
Authors: Josephine A Hinneh; Joanna L Gillis; Nicole L Moore; Lisa M Butler; Margaret M Centenera Journal: Front Oncol Date: 2022-08-10 Impact factor: 5.738