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    Molecular cancer. 2015 Mar 18. doi: 10.1186/s12943-015-0330-4. pii: 10.1186/s12943-015-0330-4. pmc: PMC4405849
    The calcium-sensing receptor suppresses epithelial-to-mesenchymal transition and stem cell- like phenotype in the colon.
    Aggarwal A1,  Prinz-Wohlgenannt M2,  Gröschel C3,  Tennakoon S4,  Meshcheryakova A5,  Chang W6,  Brown EM7,  Mechtcheriakova D8,  Kállay E9
    Author information
    1Department of Pathophysiology and Allergy Research, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. abhishek.aggarwal@meduniwien.ac.at.
    2Department of Pathophysiology and Allergy Research, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. max.wohlgenannt@gmx.at.
    3Department of Pathophysiology and Allergy Research, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. charlotte.groeschel@meduniwien.ac.at.
    4Department of Pathophysiology and Allergy Research, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. samawansha.tennakoon@meduniwien.ac.at.
    5Department of Pathophysiology and Allergy Research, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. anastasia.meshcheryakova@meduniwien.ac.at.
    6Endocrine Research Unit, Department of Veteran Affairs Medical Center, University of California, San Francisco, CA, USA. wenhan.chang@ucsf.edu.
    7Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, MA, USA. embrown@partners.org.
    8Department of Pathophysiology and Allergy Research, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. diana.mechtcheriakova@meduniwien.ac.at.
    9Department of Pathophysiology and Allergy Research, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. enikoe.kallay@meduniwien.ac.at.
    Abstract

    BACKGROUND: The calcium sensing receptor (CaSR), a calcium-binding G protein-coupled receptor is expressed also in tissues not directly involved in calcium homeostasis like the colon. We have previously reported that CaSR expression is down-regulated in colorectal cancer (CRC) and that loss of CaSR provides growth advantage to transformed cells. However, detailed mechanisms underlying these processes are largely unknown.

    METHODS AND RESULTS: In a cohort of 111 CRC patients, we found significant inverse correlation between CaSR expression and markers of epithelial-to-mesenchymal transition (EMT), a process involved in tumor development in CRC. The colon of CaSR/PTH double-knockout, as well as the intestine-specific CaSR knockout mice showed significantly increased expression of markers involved in the EMT process. In vitro, stable expression of the CaSR (HT29(CaSR)) gave a more epithelial-like morphology to HT29 colon cancer cells with increased levels of E-Cadherin compared with control cells (HT29(EMP)). The HT29(CaSR) cells had reduced invasive potential, which was attributed to the inhibition of the Wnt/β-catenin pathway as measured by a decrease in nuclear translocation of β-catenin and transcriptional regulation of genes like GSK-3β and Cyclin D1. Expression of a spectrum of different mesenchymal markers was significantly down-regulated in HT29(CaSR) cells. The CaSR was able to block upregulation of mesenchymal markers even in an EMT-inducing environment. Moreover, overexpression of the CaSR led to down-regulation of stem cell-like phenotype.

    CONCLUSIONS: The results from this study demonstrate that the CaSR inhibits epithelial-to-mesenchymal transition and the acquisition of a stem cell-like phenotype in the colon of mice lacking the CaSR as well as colorectal cancer cells, identifying the CaSR as a key molecule in preventing tumor progression. Our results support the rationale to develop new strategies either preventing CaSR loss or reversing its silencing.


    Publikations ID: 25879211
    Quelle: öffnen
     
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