title: The calcium-sensing receptor suppresses epithelial-to-mesenchymal transition and stem cell- like phenotype in the colon.
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.
  
  
  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.
authors: Department of Pathophysiology and Allergy Research, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. abhishek.aggarwal@meduniwien.ac.at.
authors: Abhishek
authors: A
authors: Aggarwal
authors: Department of Pathophysiology and Allergy Research, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. max.wohlgenannt@gmx.at.
authors: Maximilian
authors: M
authors: Prinz-Wohlgenannt
authors: Department of Pathophysiology and Allergy Research, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. charlotte.groeschel@meduniwien.ac.at.
authors: Charlotte
authors: C
authors: Gröschel
authors: Department of Pathophysiology and Allergy Research, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. samawansha.tennakoon@meduniwien.ac.at.
authors: Samawansha
authors: S
authors: Tennakoon
authors: Department of Pathophysiology and Allergy Research, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. anastasia.meshcheryakova@meduniwien.ac.at.
authors: Anastasia
authors: A
authors: Meshcheryakova
authors: Endocrine Research Unit, Department of Veteran Affairs Medical Center, University of California, San Francisco, CA, USA. wenhan.chang@ucsf.edu.
authors: Wenhan
authors: W
authors: Chang
authors: Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, MA, USA. embrown@partners.org.
authors: Edward M
authors: EM
authors: Brown
authors: Department of Pathophysiology and Allergy Research, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. diana.mechtcheriakova@meduniwien.ac.at.
authors: Diana
authors: D
authors: Mechtcheriakova
authors: Department of Pathophysiology and Allergy Research, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. enikoe.kallay@meduniwien.ac.at.
authors: Enikö
authors: E
authors: Kállay
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D044169:Receptors, Calcium-Sensing / Q000235:genetics*; D013234:Stem Cells / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: D015820:Cadherins; D044169:Receptors, Calcium-Sensing; D051176:beta Catenin; D019938:Cyclin D1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3