From Metabolism to Malignancy: Profiling Diabetes-Related Genes in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) and diabetes mellitus both affect the liver, a key metabolic organ. This study uses bioinformatics to explore genetic links between Type 1 Diabetes (T1D) and HCC prognosis. Eleven HCC gene expression datasets from GEO and one TCGA-LIHC dataset were analyzed. Gene Set Enrichment Analysis (GSEA) identified up- and downregulated genes after data normalization in R. Four datasets (GSE64041, GSE78737, GSE107170, TCGA) revealed increased expression of T1D-related genes. Ten genes, including HLA-DOB and HLA-DPB1, were consistently upregulated. Statistical analysis (Kruskal-Wallis and Mann-Whitney U tests) showed these two genes were significantly associated with tumor grade and T-stage, with p-values ranging from 0.008 to 0.019. Co-expression analysis with 96 literature-curated T1D genes identified 23 related genes. Survival analysis using Kaplan-Meier curves highlighted five genes (IL7R, CD69, CCR5, RUNX3, PRF1), with CD69 showing strong associations with T-stage and disease-free survival. PRF1, RUNX3, and CCR5 were also linked to survival outcomes. Seven diabetes-related GEO datasets were used for validation. GSEA showed T1D gene enrichment in two datasets (GSE228267, GSE232310), with HLA-DOB significantly expressed in GSE228267 (p = 0.004). These findings suggest that HLA-DOB, HLA-DPB1, and three other T1D-related genes may serve as potential biomarkers for understanding the genetic connection between T1D and HCC. Though computational, this study lays the groundwork for future experimental validation.