NETO2 Is Deregulated in Breast, Prostate, and Colorectal Cancer and Participates in Cellular Signaling

Abstract

The <i>NETO2</i> gene (neuropilin and tolloid-like 2) encodes a protein that acts as an accessory subunit of kainate receptors and is predominantly expressed in the brain. Upregulation of <i>NETO2</i> has been observed in several tumors; however, its role in tumorigenesis remains unclear. In this study, we investigated <i>NETO2</i> expression in breast, prostate, and colorectal cancer using quantitative PCR (qPCR), as well as the effect of shRNA-mediated <i>NETO2</i> silencing on transcriptome changes in colorectal cancer cells. In the investigated tumors, we observed both increased and decreased <i>NETO2</i> mRNA levels, presenting no correlation with the main clinicopathological characteristics. In HCT116 cells, <i>NETO2</i> knockdown resulted in the differential expression of 17 genes and 2 long non-coding RNAs (lncRNAs), associated with the upregulation of circadian rhythm and downregulation of several cancer-associated pathways, including Wnt, transforming growth factor (TGF)-β, Janus kinase (JAK)-signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathways. Furthermore, we demonstrated the possibility to utilize a novel model organism, short-lived fish <i>Nothobranchius furzeri</i>, for evaluating <i>NETO2</i> functions. The ortholog <i>neto2b</i> in <i>N. furzeri</i> demonstrated a high similarity in nucleotide and amino acid sequences with human <i>NETO2</i>, as well as was characterized by stable expression in various fish tissues. Collectively, our findings demonstrate the deregulation of <i>NETO2</i> in the breast, prostate, and colorectal cancer and its participation in the tumor development primarily through cellular signaling.