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

Abstract

CSDE1 (cold shock domain containing E1) gene 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. We firstly evaluated UNR/CSDE1 expression in human colon cancer derived cell lines and patient samples. Subsequently, we performed functional experiments by UNR/CSDE1 downregulation. We also evaluated UNR/CSDE1 prognostic relevance in two independent sets of patients. Not only was UNR/CSDE1 expression 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. Downregulation of UNR/CSDE1 reduced cell viability and migration throughout a restrain of epithelial-to-mesenchymal transition and increases sensitivity to apoptosis. Interestingly, high UNR/CSDE1 expression was associated with poor prognosis and correlated positively with c-MYC expression in colorectal cancer samples and cell lines. Here, we show for the first time compelling data reporting the oncogenic role of UNR/CSDE1 in human colorectal cancer.

RNA-binding proteins in tumor progression

“…The specific domains of UNR can bind to mRNA (IRES) and thus change its structure to a more powerful translation [107]. UNR has been reported to regulate the expression of c-fos, c-Myc and other protooncogenes [108]. UNR is mainly located in the cytoplasm to regulate the transcription, translation and stability of mRNA [109].…”

The role of CSDE1 in translational reprogramming and human diseases

“…Studies in a mouse model further suggested that depletion of CSDE1 strikingly reduced the metastasis to the lung, which is a frequent metastatic site for melanoma [15]. In human colorectal cancer (CRC), CSDE1 promoted cancer cell survival, invasion, and resistance to apoptosis [80]. CSDE1 was also overexpressed by an average of almost 3fold in tumour samples compared with their adjacent normal tissues in CRC patients.…”

“…Furthermore, knocking down CSDE1 in CRC cells decreased viability and the migration ratio by approximately 40%. As a treatment, downregulating CSDE1 increased the camptothecin response in CRC-derived cell lines and CRC patients [80]. High expression of CSDE1 was associated with poor prognosis in glioma and pancreatic ductal adenocarcinoma (PDAC) [16].…”

Cold Shock Domain Containing E1 (CSDE1) Protein is Overexpressed and Can be Targeted to Inhibit Invasiveness in Pancreatic Cancer Cells

“…[ 4 ] CSDE1 is localized primarily in the cytoplasm where it regulates mRNA translation and stability. [ 4 ] The oncogenic properties of CSDE1 have recently been reported in melanoma, [ 5 ] pheochromocytoma, and paraganglioma [ 6 ] as well as colorectal cancer [ 7 ] and appear to be related to the regulation of translation by CSDE1. The role of CSDE1 in PDAC has not yet been addressed, although gene expression of CSDE1 has been suggested to have some prognostic value.…”

“…[ 5 ] High CSDE1 expression is associated with poor prognosis and correlated positively with c‐MYC expression in colorectal cancer. [ 7 ] Our finding, although not providing a precise molecular mechanism, extends the involvement of CSDE1 to the control of pancreatic cancer development and more specifically its requirement for pancreatic cancer cell invasiveness.…”