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. 2021 Apr 17;158(1):14.
doi: 10.1186/s41065-021-00177-x.

Identification of metabolism genes related to hepatocarcinogenesis and progression in type 2 diabetes mellitus via co-expression networks analysis

Yiming Bi  1 , Bei Yin  1 , Guanjie Fan  2
Affiliations

Identification of metabolism genes related to hepatocarcinogenesis and progression in type 2 diabetes mellitus via co-expression networks analysis

Yiming Bi et al. Hereditas. .

Abstract

Background: Type 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.

Methods: The 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.

Results: A 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.

Conclusions: The 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.

Keywords: Hepatocellular carcinoma; Metabolism genes; Type 2 diabetes mellitus; WGCNA.

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Conflict of interest statement

No conflicts of interest in this work are declared by the authors.

Figures

Fig. 1
Fig. 1
a and b The volcano plots of T2DM and HCC. c and d The GO terms in T2DM and HCC. e and f The KEGG analysis of upregulated genes and downregulated genes in T2DM and HCC
Fig. 2
Fig. 2
a and b Hierarchical clustering dendrogram of T2DM and heatmap plot of correlation between modules and clinical traits of T2DM. c and d Hierarchical clustering dendrogram of HCC and heatmap plot of correlation between modules and clinical traits of HCC. e The correlation analysis between each module in T2DM and HCC. f and g The GO analysis of genes in modules related to T2DM and HCC
Fig. 3
Fig. 3
a to h The expressions of ACAT1, CRYL1, SLC2A2, PCK, ABAT, ACADSB, ST3GAL6 and EPHX2 based on tumor grade. i to p The expressions of ACAT1, CRYL1, SLC2A2, PCK1, ABAT, ACADSB, ST3GAL6 and EPHX2 based on metastasis status. q The correlation between genes expression and HCC survival
Fig. 4
Fig. 4
a The expression level of prognostic genes in HCC and normal samples. b The expression level of prognostic genes in HCC dataset. c The expression level of prognostic genes in T2DM datasets. d The expression level of prognostic genes in another T2DM dataset GSE50397. e The expression level of prognostic genes in another HCC dataset GSE69850
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