Liver cancer cell lines distinctly mimic the metabolic gene expression pattern of the corresponding human tumours

Abstract

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.

Metabolomic Alterations in Thyrospheres and Adherent Parental Cells in Papillary Thyroid Carcinoma Cell Lines: A Pilot Study

“…Our data indicate that metabolic alterations may contribute to the functional differences between these two tumor cell populations with different biological roles. Although the use of an in vitro model of PTC is a limit to our approach, the recent report that cancer cell lines distinctly mimic the metabolic gene expression pattern of the corresponding human tumors in liver [ 27 ] support the translation of our results, which for the first time indicate that cancer stem-like cells isolated from PTC-derived cell lines may be distinguished from the adherent cell population by a metabolomic approach, paving the road for in vivo studies.…”

ACADSB regulates ferroptosis and affects the migration, invasion, and proliferation of colorectal cancer cells

“…As a member of the acyl-CoA dehydrogenase family, ACADSB promotes the lipid metabolism via catalyzing the dehydrogenation of acyl-CoA derivatives (Arden et al, 1995). Earlier studies indicated that ACADSB might exert tumor suppressive function in poorly-differentiated hepatocellular carcinoma and kidney renal clear cell carcinoma (Nwosu et al, 2018;B. Zhang et al, 2019).…”

“…It is demonstrated that ACADSB has the greatest activity towards the short-branched-chain acyl-CoA derivative, (S)-2-methylbutyryl-CoA, but also reacts with other 2-methyl branched-chain substrates and with short straight chain acyl-CoAs (Schwander et al, 2018). Nwosu et al (2018) reported that poorly-differentiated hepatocellular carcinoma cells showed low gene expression of ACADSB. B.…”

Dual RNA-Seq characterization of host and pathogen gene expression in liver cells infected with Crimean-Congo Hemorrhagic Fever Virus

“…HepG2 and Huh7 are well-differentiated hepatocarcinoma cell lines derived from a pediatric hepatoblastoma and an adult hepatocarcinoma biopsy, respectively [18][19][20][21].Cells were generously provided by Dr. Jordan Feld, Toronto Centre for Liver Disease, Toronto General Hospital and Dr. Michael Carpenter, Viral Diseases Division, National Microbiology Laboratory; and were maintained in Dulbecco's modified eagle media, supplemented with 10% fetal bovine serum, 2mM L-glutamine, and penicillin (100 IU/ml)/streptomycin (100μg/ml). All infection studies used Crimean Congo Hemorrhagic Fever virus (CCHFV) IbAr 10200 (accession numbers AY389508, AF467768, and CHU88410).…”