AUTHOR=Nersisyan Stepan , Novosad Victor , Engibaryan Narek , Ushkaryov Yuri , Nikulin Sergey , Tonevitsky Alexander 

TITLE=ECM–Receptor Regulatory Network and Its Prognostic Role in Colorectal Cancer

JOURNAL=Frontiers in Genetics

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.782699

DOI=10.3389/fgene.2021.782699

ISSN=1664-8021

ABSTRACT=Interactions of extracellular matrix (ECM) and cellular receptors constitute one of the crucial pathways involved in colorectal cancer progression and metastasis. With the use of bioinformatics analysis, we comprehensively evaluated the prognostic information concentrated in the genes from this pathway. First, we constructed ECM-receptor regulatory network by integrating transcription factor (TF) and 5'-isomiR interaction databases with mRNA/miRNA-seq data from The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD). Notably, one third of interactions mediated by 5'-isomiRs was represented by non-canonical isomiRs (isomiRs, whose 5'-end sequence did not match with canonical miRBase version). Then, exhaustive search-based feature selection was used to fit prognostic signatures composed of nodes from the network for overall survival prediction. Two reliable prognostic signatures were identified and validated on the independent The Cancer Genome Atlas Rectum Adenocarcinoma (TCGA-READ) cohort. The first signature was made up by six genes, directly involved in ECM-receptor interaction: AGRN, DAG1, FN1, ITGA5, THBS3, TNC (concordance index 0.61, logrank test p = 0.0164, 3-year ROC AUC = 0.68). The second hybrid signature was composed of three regulators: hsa-miR-32-5p, NR1H2, SNAI1 (concordance index 0.64, logrank test p = 0.0229, 3-year ROC AUC = 0.71). While hsa-miR-32-5p exclusively regulated ECM-related genes (COL1A2 and ITGA5), NR1H2 and SNAI1 also targeted other pathways (adhesion, cell cycle, cell division). Concordant distributions of the respective risk scores across four stages of colorectal cancer and adjacent normal mucosa additionally confirmed reliability of the models.