Abstract:Background & AimsCancer cells rely on metabolic alterations to enhance proliferation and survival. Metabolic gene alterations that repeatedly occur in liver cancer are largely unknown. We aimed to identify metabolic genes that are consistently deregulated, and are of potential clinical significance in human hepatocellular carcinoma (HCC).MethodsWe studied the expression of 2,761 metabolic genes in 8 microarray datasets comprising 521 human HCC tissues. Genes exclusively up-regulated or down-regulated in 6 or m… Show more
“…upregulation in HCC was also recently reported (Nwosu et al, 2017); however, the expression of this gene was significantly downregulated in the TCGA HCC specimens. This discrepancy awaits further investigation.…”
Section: Phase I Enzymesupporting
confidence: 77%
“…GSE62043, GSE14520, and GSE6764 are the Gene Expression Omnibus accession numbers for related studies. The upregulation of KCNJ11 (Zhang et al, 2018) and the downregulation of catalase (Cho et al, 2014), PXR , or cytidine deaminase (Nwosu et al, 2017) in HCC have been recently reported. KCNJ11 is an HCC oncogene and its overexpression in HCC promotes cell proliferation and tumor progression (Zhang et al, 2018).…”
Genes involved in drug absorption, distribution, metabolism, and excretion (ADME) are called ADME genes. Currently, 298 genes that encode phase I and II drug metabolizing enzymes, transporters, and modifiers are designated as ADME genes by the PharmaADME Consortium. ADME genes are highly expressed in the liver and their levels can be influenced by liver diseases such as hepatocellular carcinoma (HCC). In this study, we obtained RNA-sequencing and microRNA (miRNA)-sequencing data from 371 HCC patients via The Cancer Genome Atlas liver hepatocellular carcinoma project and performed ADME gene-targeted differential gene expression analysis and expression correlation analysis. Two hundred thirty-three of the 298 ADME genes (78%) were expressed in HCC. Of these genes, almost one-quarter (58 genes) were significantly downregulated, while only 6% (15) were upregulated in HCC relative to healthy liver. Moreover, one-half (14/28
“…upregulation in HCC was also recently reported (Nwosu et al, 2017); however, the expression of this gene was significantly downregulated in the TCGA HCC specimens. This discrepancy awaits further investigation.…”
Section: Phase I Enzymesupporting
confidence: 77%
“…GSE62043, GSE14520, and GSE6764 are the Gene Expression Omnibus accession numbers for related studies. The upregulation of KCNJ11 (Zhang et al, 2018) and the downregulation of catalase (Cho et al, 2014), PXR , or cytidine deaminase (Nwosu et al, 2017) in HCC have been recently reported. KCNJ11 is an HCC oncogene and its overexpression in HCC promotes cell proliferation and tumor progression (Zhang et al, 2018).…”
Genes involved in drug absorption, distribution, metabolism, and excretion (ADME) are called ADME genes. Currently, 298 genes that encode phase I and II drug metabolizing enzymes, transporters, and modifiers are designated as ADME genes by the PharmaADME Consortium. ADME genes are highly expressed in the liver and their levels can be influenced by liver diseases such as hepatocellular carcinoma (HCC). In this study, we obtained RNA-sequencing and microRNA (miRNA)-sequencing data from 371 HCC patients via The Cancer Genome Atlas liver hepatocellular carcinoma project and performed ADME gene-targeted differential gene expression analysis and expression correlation analysis. Two hundred thirty-three of the 298 ADME genes (78%) were expressed in HCC. Of these genes, almost one-quarter (58 genes) were significantly downregulated, while only 6% (15) were upregulated in HCC relative to healthy liver. Moreover, one-half (14/28
“…The current study revealed that GSTZ1‐1 expression is markedly downregulated in HCC, which contributed to tumor progression and poor prognosis, providing evidence supporting recent reports that GSTZ1‐1 is decreased in HCC (Jahn et al , ; Nwosu et al , ). Moreover, our studies demonstrated that GSTZ1‐1 plays a tumor suppressor role in HCC.…”
The
IGF
1R signaling is important in the malignant progression of cancer. However, overexpression of
IGF
1R has not been properly assessed in
HCC
. Here, we revealed that
GSTZ
1‐1, the enzyme in phenylalanine/tyrosine catabolism, is downregulated in
HCC
, and its expression was negatively correlated with
IGF
1R. Mechanistically,
GSTZ
1‐1 deficiency led to succinylacetone accumulation, alkylation modification of
KEAP
1, and
NRF
2 activation, thus promoting
IGF
1R transcription by recruiting
SP
1 to its promoter. Moreover, inhibition of
IGF
1R or
NRF
2 significantly inhibited tumor‐promoting effects of
GSTZ1
knockout
in vivo
. These findings establish succinylacetone as an oncometabolite, and
GSTZ
1‐1 as an important tumor suppressor by inhibiting
NRF
2/
IGF
1R axis in
HCC
. Targeting
NRF
2 or
IGF
1R may be a promising treatment approach for this subset
HCC
.
“…liver-specific glutaminase ( GLS2 ), complement 7 and 9 (C7/9), CXCL12, CYP1A2, CYP2E1, GYS2, HAMP, IGF1, LCAT, SLC22A1, etc, n = 1547) (Additional file 5: Table S4). Of note, AKR1B10, ACSL4, GLS2 , LCAT, were among the metabolic targets we previously identified as consistent in HCC [13], indicating a high alteration frequency of these genes across liver cancer datasets.Fig. 2Functional annotation analysis, metabolic gene and proteomic profile of HCC cell lines.…”
BackgroundAlthough metabolism is profoundly altered in human liver cancer, the extent to which experimental models, e.g. cell lines, mimic those alterations is unresolved. Here, we aimed to determine the resemblance of hepatocellular carcinoma (HCC) cell lines to human liver tumours, specifically in the expression of deregulated metabolic targets in clinical tissue samples.MethodsWe compared the overall gene expression profile of poorly-differentiated (HLE, HLF, SNU-449) to well-differentiated (HUH7, HEPG2, HEP3B) HCC cell lines in three publicly available microarray datasets. Three thousand and eighty-five differentially expressed genes in ≥2 datasets (P < 0.05) were used for pathway enrichment and gene ontology (GO) analyses. Further, we compared the topmost gene expression, pathways, and GO from poorly differentiated cell lines to the pattern from four human HCC datasets (623 tumour tissues). In well- versus poorly differentiated cell lines, and in representative models HLE and HUH7 cells, we specifically assessed the expression pattern of 634 consistently deregulated metabolic genes in human HCC. These data were complemented by quantitative PCR, proteomics, metabolomics and assessment of response to thirteen metabolism-targeting compounds in HLE versus HUH7 cells.ResultsWe found that poorly-differentiated HCC cells display upregulated MAPK/RAS/NFkB signaling, focal adhesion, and downregulated complement/coagulation cascade, PPAR-signaling, among pathway alterations seen in clinical tumour datasets. In HLE cells, 148 downregulated metabolic genes in liver tumours also showed low gene/protein expression – notably in fatty acid β-oxidation (e.g. ACAA1/2, ACADSB, HADH), urea cycle (e.g. CPS1, ARG1, ASL), molecule transport (e.g. SLC2A2, SLC7A1, SLC25A15/20), and amino acid metabolism (e.g. PHGDH, PSAT1, GOT1, GLUD1). In contrast, HUH7 cells showed a higher expression of 98 metabolic targets upregulated in tumours (e.g. HK2, PKM, PSPH, GLUL, ASNS, and fatty acid synthesis enzymes ACLY, FASN). Metabolomics revealed that the genomic portrait of HLE cells co-exist with profound reliance on glutamine to fuel tricarboxylic acid cycle, whereas HUH7 cells use both glucose and glutamine. Targeting glutamine pathway selectively suppressed the proliferation of HLE cells.ConclusionsWe report a yet unappreciated distinct expression pattern of clinically-relevant metabolic genes in HCC cell lines, which could enable the identification and therapeutic targeting of metabolic vulnerabilities at various liver cancer stages.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0872-6) contains supplementary material, which is available to authorized users.
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