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

Maria S Fedorova,Zulfiya G Guvatova,Anastasiya V Snezhkina,Irina A Ishina,Anna V Kudryavtseva,Vladislav S Pavlov,Maria V Savvateeva,Anastasiya A Kobelyatskaya,Elena A Pudova,Tatiana B Demidova,Dmitry Y Trofimov,Nadezhda N Volchenko,George S Krasnov,Anastasiya V Lipatova,Gennady T Sukhikh

doi:10.3389/fgene.2020.594933

Abstract

The NETO2 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 NETO2 has been observed in several tumors; however, its role in tumorigenesis remains unclear. In this study, we investigated NETO2 expression in breast, prostate, and colorectal cancer using quantitative PCR (qPCR), as well as the effect of shRNA-mediated NETO2 silencing on transcriptome changes in colorectal cancer cells. In the investigated tumors, we observed both increased and decreased NETO2 mRNA levels, presenting no correlation with the main clinicopathological characteristics. In HCT116 cells, NETO2 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 Nothobranchius furzeri, for evaluating NETO2 functions. The ortholog neto2b in N. furzeri demonstrated a high similarity in nucleotide and amino acid sequences with human NETO2, as well as was characterized by stable expression in various fish tissues. Collectively, our findings demonstrate the deregulation of NETO2 in the breast, prostate, and colorectal cancer and its participation in the tumor development primarily through cellular signaling.

Highlights

NETO2 was first described in 2001 as a gene demonstrating significant similarity to NETO1 (Stohr et al, 2002)
NETO2 gene expression was increased in 31% of cases (2–24-fold), with decreased mRNA levels detected in 44% of samples (2–18-fold) (Table 1)
We first demonstrated the deregulation of NETO2 expression in breast and prostate cancer

Summary

Introduction

NETO2 (neuropilin and tolloid-like 2) was first described in 2001 as a gene demonstrating significant similarity to NETO1 (Stohr et al, 2002). Both genes encode putative transmembrane proteins containing two CUB domains, followed by a low-density lipoprotein class A (LDLa) module in the extracellular region and conserved FXNPXY-like motif in the cytoplasmic region. This structure of NETO proteins suggested their possible role in intracellular signaling pathways. A series of reports have shown the expression of NETO2 in the brain, as well as its involvement in the modulation of most kainate receptors (KARs) (Straub et al, 2011) and N-methyl-D-aspartate (NMDA) receptors (Wyeth et al, 2014). NETO2 and its paralog NETO1 are widely recognized as the main auxiliary subunits of KARs

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Conclusion