EPDR1 up-regulation in human colorectal cancer is related to staging and favours cell proliferation and invasiveness

Abstract

The finding of novel molecular markers for prediction or prognosis of invasiveness in colorectal cancer (cRc) constitutes an appealing challenge. Here we show the up-regulation of EPDR1 in a prospective cohort of 101 CRC patients, in a cDNA array of 43 patients and in in silico analyses. EPDR1 encodes a protein related to ependymins, a family of glycoproteins involved in intercellular contacts. A thorough statistical model allowed us to conclude that the gene is significantly up-regulated in tumour tissues when compared with normal mucosa. these results agree with those obtained by the analysis of three publicly available databases. EPDR1 up-regulation correlates with the tnM staging parameters, especially t and M. Studies with cRc cell lines revealed that the methylation of a cpG island controls EPDR1 expression. siRNA knocking-down and overexpression of the gene following transient plasmid transfection, showed that EPDR1 favours cell proliferation, migration, invasiveness and adhesion to type I collagen fibres, suggesting a role in epithelial to mesenchymal transition. Both statistical and functional analysis correlated EPDR1 overexpression with invasiveness and dissemination of tumour cells, supporting the inclusion of EPDR1 in panels of genes used to improve molecular subtyping of cRc. eventually, EPDR1 may be an actionable target. Colorectal cancer (CRC) is one of the most common malignancies worldwide 1. In spite of the progresses of precision medicine, the long-term survival of patients with advanced metastatic disease is still poor 2 and the burden of CRC is expected to increase by 60% in the next decade 1. Nevertheless, this disease is a good candidate for screening programmes 3 and its early detection improve treatment and survival. Most of CRC-related death is due to tumour metastasis 4 and, therefore, finding of molecular markers for prediction or prognosis of invasiveness, which could be added to the available repertoire of potential markers 5-7 , constitutes an appealing challenge. This is particularly attractive in view of the growing interest in improving the clinical stratification of CRC 8,9. This reason, together with the risks of metastatic dissemination, makes especially interesting the identification of potential actionable targets in CRC. The EPDR1 gene codes for a protein related to ependymins, a family of piscine brain glycoproteins 10. Ependymins, encoded by Epd genes, are transmembrane proteins that play a role in intercellular contacts between neural cells 11. It was early suggested that their extracellular domain may display antiadhesive properties 12 and it shows a calcium-dependent ability to interact with collagen fibrils 13 .

EPDR1 is related to stages and metastasize in bladder cancer and can be used as a prognostic biomarker

“…Afterward, Kirkland et al [ 6 ] also found a gene highly expressed in hematopoietic cells and several malignant tissues and cell lines, which was named MERP1 and turned out to be the same as UCC1. Lately, several studies [ 7 – 9 ] were reported that EPDR1 was closely related to pathological or developmental processes of various tumors including breast cancer (BRCA) [ 10 ], hepatocellular carcinoma (HCC) [ 11 ], colorectal cancer, and so on.…”

ADAMTS14, ARHGAP22, and EPDR1 as potential novel targets in acute myeloid leukaemia

“…Likewise, searching the TCGA, PanCancer Atlas database [21] for the candidate genes revealed that ADAMTS14 was not reported amongst the mutated genes; however, other ADAMTS isoforms were found to be mutated in these patients' samples, including ADAMTS 1, 6, 9, 12, and 16-19. Similarly, other ARHGAP isoforms were mutated in these patients (ARHGAP 5,6,18,21,(24)(25)(26)31,32,35,36,39,40,and 44). A deletion alteration in ARHGAP 22 was also reported in only 0.5% of patients (10q11.22-q).…”

“…The third proposed candidate, EPDR1 , was originally identified as a batokine with a potentially important role in metabolic regulation. Recently, overexpression of this protein was found to be positively correlated with colorectal cancer proliferation and invasiveness in a cohort study [ 32 ]. Similarly, high levels of EPDR1 are correlated with the advancement of hepatocellular carcinoma stages, making it a potential biomarker for disease progression and monitoring [ 33 ].…”

EPDR1, Which Is Negatively Regulated by miR-429, Suppresses Epithelial Ovarian Cancer Progression via PI3K/AKT Signaling Pathway

“…Gimeno-Valiente et al. ( 11 ) found that upregulation of EPDR1 in DLD1 and HCT116 cell lines was related to human colorectal cancer stage, and knockdown of EPDR1 could inhibit cell proliferation, migration, invasiveness, and adhesion to type I collagen fibers. Similar results were observed in human bladder cancer ( 17 ).…”

“…Although the function of EPDR1 has not been completely characterized, accumulating evidence suggests that EPDR1 is associated with various human diseases, particularly the initiation and progression of various human cancers ( 9 , 10 ). At present, EPDR1 has been reported to be differentially expressed in a variety of tumors and exerts an oncogenic role in colorectal cancer ( 11 ) and a tumor-suppressive role in breast cancer ( 12 ). However, the characterization of EPDR1 gene in EOC has not been reported.…”