Identification of four novel hub genes as monitoring biomarkers for colorectal cancer

Abstract

Background It must be admitted that the incidence of colorectal cancer (CRC) was on the rise all over the world, but the related treatment had not caught up. Further research on the underlying pathogenesis of CRC was conducive to improving the survival status of current CRC patients. Methods Differentially expressed genes (DEGs) screening were conducted based on “limma” and “RobustRankAggreg” package of R software. Weighted gene co-expression network analysis (WGCNA) was performed in the integrated DEGs that from The Cancer Genome Atlas (TCGA), and all samples of validation were from Gene Expression Omnlbus (GEO) dataset. Results The terms obtained in the functional annotation for primary DEGs indicated that they were associated with CRC. The MEyellow stand out whereby showed the significant correlation with clinical feature (disease), and 4 hub genes, including ABCC13, AMPD1, SCNN1B and TMIGD1, were identified in yellow module. Nine datasets from Gene Expression Omnibus database confirmed these four genes were significantly down-regulated and the survival estimates for the low-expression group of these genes were lower than for the high-expression group in Kaplan-Meier survival analysis section. MEXPRESS suggested that down-regulation of some top hub genes may be caused by hypermethylation. Receiver operating characteristic curves indicated that these genes had certain diagnostic efficacy. Moreover, tumor-infiltrating immune cells and gene set enrichment analysis for hub genes suggested that there were some associations between these genes and the pathogenesis of CRC. Conclusion This study identified modules that were significantly associated with CRC, four novel hub genes, and further analysis of these genes. This may provide a little new insights and directions into the potential pathogenesis of CRC.

TMIGD1: Emerging functions of a tumor supressor and adhesion receptor

“…TMIGD1 is a cell adhesion receptor that has drawn attention after the discovery that its expression is progressively downregulated during the development of colorectal cancer in humans [ 16 ]. Meanwhile, a number of studies have confirmed a highly significant downregulation not only in colorectal cancer but also in renal cancer, strongly supporting a tumor-suppressive function of TMIGD1 and suggesting that TMIGD1 expression may be used as a prognostic marker [ 19 , 63 , 69 ]. Also, the molecular biology underlying its functions is beginning to be understood.…”

“…A RNAseq-based comparison of hyperplastic polyp lesions with colorectal adenoma lesions identified TMIGD1 among the top 10 down-regulated genes in colorectal adenoma [ 68 ], confirming a gradual downregulation of TMIGD1 expression during the development of colon cancer. Another analysis using CRC-derived microarrays that were based on 369 carcinoma samples from 9 different datasets of different geographical origin identified TMIGD1 as one among 22 hub genes whose downregulation in CRC samples was most significant [ 69 ]. Additional observations describing reduced TMIGD1 expression in CRC samples were made in studies comparing colonic non-adenomatous, non-neoplastic tissue with colonic tumor tissue, with TMIGD1 being among the 11 most significantly downregulated genes in colonic tumor tisse [ 70 ].…”

“…Additional observations based on microarray analyses and on bioinformatic analyses of published datasets further confirmed a downregulation of TMIGD1 expression in human colorectal cancer [ 19 , 63 ]. In addition, several studies find that low TMIGD1 expression levels in tumors of CRC patients correlate with lower survival rates of the patients [ 19 , 63 , 69 ]. Mice with a constitutive inactivation of the Tmigd1 gene have an altered intestinal tissue morphology and develop intestinal adenoma [ 19 ], strongly suggesting that low TMIGD1 levels are not just correlative but rather causative for colorectal cancer development.…”

Membrane recruitment of the polarity protein Scribble by the cell adhesion receptor TMIGD1

“…A role of TMIGD1 in recruiting Scrib to the lateral membrane is consistent with a predicted function of TMIGD1 as tumor suppressor protein. Several unbiased studies describe a strong and highly significant reduction of TMIGD1 gene expression in colon cancer in humans 72 – 75 with a progressive downregulation during disease progression 21 , 76 . Also, several studies found a significant downregulation of TMIGD1 gene expression in diseases associated with chronic intestinal inflammation such as Crohn’s disease or inflammatory bowel disease 26 , 73 , 77 , conditions which promote carcinogenesis 78 .…”

Methods in DNA methylation array dataset analysis: A review

“…The majority of the articles utilize web-based tools for validation. For instance, Luo D et al, 2022 used the MEXPRESS web-based tool to visualize the relationship between gene expression and methylation extend in hub genes related to Colorectal cancer [115] . Tong Lin et al, 2021 employed DNMIVD, SurvivalMeth, and MethServ tools for estimating the correlation between the expression level and the methylation density of DEGs, estimating the global methylation, and finding an association between the methylation level of CpG sites of the DEGs and overall survival of hepatocellular carcinoma patients, respectively [116] .…”