Abstract
BackgroundType 2 Diabetes Mellitus (T2DM) is an independent risk factor of hepatocellular carcinoma (HCC). However, the related genes and modules to hepatocarcinogenesis and progression in T2DM remain unclear.MethodsThe microarray data from Gene Expression Omnibus (GEO) were analyzed to screen differentially expressed genes (DEGs) of T2DM and HCC dataset. Then, weighted gene co-expression network analysis (WGCNA) was performed on these DEGs to detect the modules and genes, respectively. Common genes in modules with clinical interests of T2DM and HCC were obtained and annotated via GOSemSim package and Metascape. Genes related to late-stage HCC and high glycated haemoglobin (HbA1c) were also identified. These genes were validated by UALCAN analysis and univariate cox regression based on The Cancer Genome Atlas (TCGA). Finally, another two independent datasets were applied to confirm the results of our study.ResultsA total of 1288 and 1559 DEGs of T2DM and HCC were screened, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment revealed several shared pathways in two diseases, such as pathways in cancer and metabolism. A total of 37 common genes correlated with T2DM and HCC were then identified with WGCNA. Furthermore, 12 genes from modules associated with late-stage HCC and high HbA1c were regarded as hub genes. Among these genes, 8 genes associated with tumor invasion and metastasis were validated by UALCAN analysis. Moreover, downregulations of ACAT1, SLC2A2, PCK1 and ABAT were significantly associated with poorer prognosis in HCC patients with elevated HbA1c. Additionally, the expressions of PCK1 and ABAT were raised in HepG2 cells pre-treated with metformin and phenformin.ConclusionsThe present study confirmed several metabolic genes related to hyperglycemia and malignant tumor, which may provide not only new insights into the pathogenesis of hepatocarcinogenesis and progression in T2DM, but also novel therapeutic targets for T2DM patients with HCC in the future.
Highlights
Type 2 Diabetes Mellitus (T2DM) is an independent risk factor of hepatocellular carcinoma (HCC)
Identification and functional enrichment of differentially expressed genes (DEGs) A total of 1288 DEGs were screened between T2DM and normal controls, whereas 1559 DEGs were obtained between HCC and the normal samples
The upregulated DEGs in T2DM and HCC were enriched in pathways in cancer and extracellular matrix (ECM)-recptor interaction, whereas the downregulated DEGs were enriched in metabolic pathways and amino acids degradation (Fig. 1e and f )
Summary
Type 2 Diabetes Mellitus (T2DM) is an independent risk factor of hepatocellular carcinoma (HCC). Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide. The risk of HCC development is positively correlated with T2DM duration, which significantly increases to 7.52 times in individuals with a 10-year-duration of diabetes [5]. A number of studies reported that treatment with glucose-lowering medications like metformin could improve the survival rate of patients with HCC [8]. These shreds of evidence revealed that T2DM had turned into an independent risk factor for HCC development
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