Identification of ceRNA-based H19/SIX4 regulatory axis as a prognostic biomarker for colorectal cancer via high throughput transcriptomic data

Abstract

Abstract Colorectal cancer, a common digestive system malignancy, is a leading cause of cancer-related deaths worldwide and has become a major public health problem. Molecular research can provide a large amount of new information for cancer treatment and new drug development. The ceRNA (competing endogenous RNAs) hypothesis reveals a mechanism of RNA interactions. This research aims to construct a ceRNA regulatory network in colorectal cancer to identify potential prognostic biomarkers associated with COAD. Expression profiles of COAD were downloaded from The Cancer Genome Atlas (TCGA). We used R software for differential analysis and enrichment analysis and then identified the subcellular localization of lncRNAs using the LncATLAS and LncACTdb database. Next, we constructed ceRNA networks using Cytoscape software and used survival analysis to identify the ceRNA axis with prognostic significance. The results showed that the H19/miR-193b-3p/SIX4 ceRNA network was associated with COAD prognosis. The correlation between SIX4 expression and tumor immune infiltration was explored via TIMER. The GeneMANIA database was used to obtain proteins interacting with SIX4, and these proteins were subjected to GO and KEGG enrichment analysis, which showed that these proteins are involved in “Transcription misregulation in cancer” of tumors. Then, the relationship between SIX4 expression and prognosis was analyzed using univariate cox regression analysis, plotting forest plots, and plotting K-M curves. The expression and correlation of SIX4 with tumor mutational burden (TMB), microsatellite instability (MSI), DNA mismatch repair genes (MMRs), and methyltransferases in pan-cancer were analyzed. The results indicated that the H19/miR-193b-3p/SIX4 ceRNA axis probably influences the alteration of the tumor immune microenvironment. In addition, the GSEA results showed that high expression of SIX4 was mainly associated with the “Notch signaling pathway”.