LAT, HOXD3 and NFE2L3 identified as novel DNA methylation-driven genes and prognostic markers in human clear cell renal cell carcinoma by integrative bioinformatics approaches

Abstract

Background: Abnormal DNA methylation of is one of the important mechanisms leading to tumor pathogenesis. The purpose of this study was to explore differentially methylated genes that may drive the development of renal clear cell carcinoma through a comprehensive analysis of the TCGA database. Materials and methods: Methylation data and RNA-seq data for clear cell renal cell carcinoma were downloaded from The Cancer Genome Atlas (TCGA). Differentially methylated genes and the differential genes associated with survival were then screened by MethylMix R package and univariate Cox proportional-hazards model, respectively. Their common genes were then intersected and obtained for further analysis. Correlation of gene expression and methylation levels, gene set enrichment analysis (GSEA) enrichments, survival curve, and ROC curve plotting for DNA methylation-driven genes were finally performed. The methylation alterations of the three genes were validated via two GEO datasets (GSE70303 and GSE113501), and the genes expression level was verified through two GEO datasets (GSE6344 and GSE53757). Results: Three novel DNA methylation-driven genes LAT, HOXD3 and NFE2L3 were identified in clear cell renal cell carcinoma. Expression analysis further revealed that hypomethylation levels of LAT and NFE2L3 showed higher gene expression levels, while HOXD3 exhibited opposite methylation-expression pattern. The CpG sites of LAT (cg16462073), HOXD3 (cg24000528) and NFE2L3 (cg16882373) that may affect respective gene expressions were also identified. For the survival analysis, we found that hypomethylation and over-expression of LAT and NFE2L3 were correlated with poor survival, while hypermethylation and low-expression HOXD3 was correlated with poor survival of clear cell renal cell carcinoma patients. In addition, GSEA KEGG analysis and biological processes of these genes were also enriched for functional analysis. Kaplan-Meier survival and ROC analyses of these genes showed an average risk score of 0.9140593, AUC = 0.692, which suggested a good clinical application value. Finally, the opposite methylation-expression pattern of these three genes were verified in GEO datasets. Conclusions: In this study, we successfully exhibited the potential DNA methylation-driven genes LAT, HOXD3, and NFE2L3 involved in clear cell renal cell carcinoma. Moreover, gene functions and prognostic risk models were also elucidated, which facilitated the expansion of the current study on the role of methylation in the pathology process of clear cell renal cell carcinoma.

A ceRNA-associated risk model predicts the poor prognosis for head and neck squamous cell carcinoma patients

“…T cell is an important component of acquired immunity for hosts, which is able to be activated by phosphorylated LAT through TCR signaling pathway 38 . Wang et al elucidated prognostic risk models containing 3 genes by comprehensively analyzing methylation data and RNA-seq data for clear cell renal cell carcinoma (ccRCC) from TCGA database, and concluded that hypomethylation and over-expression of LAT resulted in poor OS of ccRCC 39 . Nevertheless, no studies so far have reported any correlation between LAT and HNSCC.…”

Methylation-Driven Genes Identified as Novel Prognostic Indicators for Thyroid Carcinoma

“…For example, Long et al used two DNA methylation-driven genes, SPP1 and LCAT, to construct two-gene signature which acted as an independent predictor for prognosis of liver cancer (Long et al, 2019). Methylated hub genes, including HOXD3, LAT, and NFE2L3, were proved to be a novel prognostic indicators in clear cell renal cell carcinoma (Wang et al, 2019). However, to our best knowledge, there is still a lack of research on screening DNA methylation-driven genes as prognostic biomarker in thyroid cancer.…”

In VitrotoIn VivoConcordance of Toxicity Using the Human Proximal Tubule Cell Line HK-2

“…Within each of the 6 categories of selected toxins, variation was observed in the extent of their potency against HK-2 cells, but overall, anticancer drugs and heavy metal-containing compounds were the most toxic. Within the anticancer drug category, in vivo animal and clinical studies have demonstrated potentially profound proximal tubular nephrotoxicity of idarubicin, 23,24 camptothecin, 25,26 vinblastine sulfate, 27 mitomycin C, 28,29 taxol, 30 doxorubicin-HCl, 24,31 sunitinib malate, 32,33 methotrexate hydrate, 28,34 and afatinib 35,36 These pharmaceutical drugs which possess vastly different mechanisms of action for their intended purposes of affecting the tubular and other parts of the kidney are not well studied. However, what they have in common is that these drugs and their metabolites are commonly eliminated through the renal system.…”