UNR/ <i>CSDE1</i> Expression Is Critical to Maintain Invasive Phenotype of Colorectal Cancer Through Regulation of c-MYC and Epithelial-to-Mesenchymal Transition

Abstract

Background: CSDE1 is located upstream of the N-RAS locus, and codes for an RNA-binding protein named Upstream of N-Ras (UNR). In cancer, CSDE1 has been shown to regulate c-fos, c-myc, pten, rac1 or vimentin. UNR/CSDE1 has been studied in breast, melanoma, pancreatic and prostate cancer. Then, the aim of this study is to evaluate the role of CSDE1/UNR in colorectal cancer progression and maintenance of aggressive phenotype. Methods: For this, we firstly evaluated UNR/CSDE1 expression in human colon cancer derived cell lines, and patient samples. Not only UNR/CSDE1 expression was higher in tumor samples compared to untransformed samples, but also in colonospheres and metastatic origin cell lines than their parental and primary cell lines respectively. Subsequently, we performed functional experiments by UNR/CSDE1 downregulation. Findings: We described for the first time the oncogenic role of UNR/CSDE1 in colorectal cancer. Downregulation of UNR/CSDE1 reduced cell viability and migration throughout a restrain of epithelial-to-mesenchymal transition and increases sensitivity to apoptosis. We then evaluated UNR/CSDE1 expression in two independent set of patients: cohort I with 35 and cohort II with 222 patient samples, and we found that high UNR/CSDE1 expression was associated to poor prognosis. Interestingly, expression of UNR correlated positively with c-MYC expression in colorectal cancer samples and cell lines. Conclusion: Here, we show compelling data reporting the oncogenic role of UNR/CSDE1 in human colorectal cancer samples. Funding: This work has been carried out with the support of the RNA-Reg ConsoliderConsortium (CSD2009-00080), and by Spanish Health Research Project Funds (PI16/01468) from Instituto de Salud Carlos III -FEDER (J.G.-F.), both of the Spanish Ministry of Economy, Industry and Competitiveness. Declaration of Interest: The authors declare no potential conflicts of interest. Ethical Approval: All patients gave written informed consent for the use of their biological samples for research purposes. The institutional review board (IRB) of the Fundacion Jimenez Diaz Hospital evaluated the study, granting approval on December 9, 2014 with approval number 17/14. Moreover, fundamental ethical principles promoted by Spain (LOPD 15/1999) and the European Union Fundamental Rights of the EU (2000/C364/01) were followed. In addition, all patient´s data were processed according to Declaration of Helsinki (last revision 2013) and Spanish National Biomedical Research Law (14/2007, of July 3).