The calcium-sensing receptor suppresses epithelial-to-mesenchymal transition and stem cell- like phenotype in the colon

Molecular Cancer

Research

Edward M Brown¹  Charlotte Gröschel²  Enikö Kállay²  Maximilian Prinz-Wohlgenannt²  Abhishek Aggarwal²  Samawansha Tennakoon²  Anastasia Meshcheryakova²  Diana Mechtcheriakova²  Wenhan Chang³ 

[1] Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, MA, USA;Department of Pathophysiology and Allergy Research, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria;Endocrine Research Unit, Department of Veteran Affairs Medical Center, University of California, San Francisco, CA, USA;

关键词: Calcium-sensing receptor;    Tumor suppressor;    Colon;    Inflammation;    Cancer;    EMT;    Cancer stem cell;    Calcimimetic;   

DOI  :  10.1186/s12943-015-0330-4

 received in 2014-12-22, accepted in 2015-03-03,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundThe 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 resultsIn 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 (HT29CaSR) gave a more epithelial-like morphology to HT29 colon cancer cells with increased levels of E-Cadherin compared with control cells (HT29EMP). The HT29CaSR 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 HT29CaSR 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.ConclusionsThe 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.

【 授权许可】

Unknown   
© Aggarwal et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.