Identification of Energy Metabolism Genes for the Prediction of Survival in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) samples were clustered into three energy metabolism-related molecular subtypes (C1, C2, and C3) with different prognosis using the gene expression data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). HCC energy metabolism-related molecular subtype analysis was conducted based on the 594 energy metabolism genes. Differential expression analysis yielded 576 differentially expressed genes (DEGs) among the three subtypes, which were closely related to HCC progression. Six genes were finally selected from the 576 DEGs through LASSO-Cox regression and used in constructing a six-gene signature-associated prognostic risk model, which was validated using the TCGA internal and three GEO external validation cohorts. The risk model showed that high ANLN, ENTPD2, TRIP13, PLAC8, and G6PD expression levels were associated with bad prognosis, and high expression of ADH1C was associated with a good prognosis. The validation results showed that our risk model had a high distinguishing ability of prognosis in HCC patients. The four enriched pathways of the risk model were obtained by gene set enrichment analysis (GSEA) and found to be associated with the tumorigenesis and development of HCC, including the cell cycle, Wnt signaling pathway, drug metabolism cytochrome P450, and primary bile acid biosynthesis. The risk score calculated from the established risk model in 204 samples and other clinical characteristics were used in building a nomogram with a good prognostic prediction ability (C-index = 0.746, 95% CI = 0.714-0.777). The area under the curves (AUCs) of the nomogram model in 1-, 2-, and 3-years were 0.82, 0.77, and 0.79, respectively. Then, qRT-PCR and immunohistochemistry were used to validate the mRNA expression levels of the six genes, and significant differences in mRNA and gene expression were observed among the tumor and adjacent tissues. Overall, our study divided HCC patients into three energy metabolism-related molecular subtypes with different prognosis. Then, a risk model with a good performance in prognostic prediction was built using the TCGA dataset. This model can be used as an independent prognostic evaluation index for HCC patients.

Identification of a Prognostic Index Based on a Metabolic-Genomic Landscape Analysis of Hepatocellular Carcinoma (HCC)

“…We also inhibited G6PD expression in HepG2 cell lines and found that G6PD knockdown could significantly repress the proliferation ability of the cells. This result is consistent with the findings of Chen et al 39 However, the relationship between HCC progression and G6PD expression has not been confirmed, and our correlation analysis between IHC staining and clinicopathological parameters might provide some clues for further research. Taken together, our results suggest that MRGs, especially G6PD, might play a role in the development and progression of HCC.…”

Prognostic implications of alcohol dehydrogenases in hepatocellular carcinoma

“…Recently, the expression of ADH1A was measured by using MS/MS and TMA in CHCC-HBV patients, which indicated the robust prognostic value of ADH1A for potential clinical application [ 34 ]. Moreover, Chen Q, et al also reported that high expression of ADH1C was associated with a good prognosis for HCC patients by using the TCGA internal and three GEO (GSE76427, GSE15654, and GSE14520) external validation cohorts [ 35 ]. In addition, the prognostic value of ADH4 was also confirmed by immunohistochemical analysis with 91 paraffin-embedded HCC specimens [ 36 ].…”

Prognostic implications of alcohol dehydrogenases in hepatocellular carcinoma

“…Recently, the expression of ADH1A was measured by using MS/MS and TMA in CHCC-HBV patients, which indicated the robust prognostic value of ADH1A for potential clinical application [34]. Moreover, Chen Q, et al also reported that high expression of ADH1C was associated with a good prognosis for HCC patients by using the TCGA internal and three GEO (GSE76427, GSE15654, and GSE14520) external validation cohorts [35]. In addition, the prognostic value of ADH4 was also con rmed by immunohistochemical analysis with 91 para n-embedded HCC specimens [36].…”