eprintid: 25460 rev_number: 35 eprint_status: archive userid: 1589 dir: disk0/00/02/54/60 datestamp: 2018-10-25 12:50:54 lastmod: 2024-03-10 03:41:19 status_changed: 2018-10-25 12:50:54 type: article metadata_visibility: show creators_name: Nwosu, Zeribe C. creators_name: Battello, Nadia creators_name: Rothley, Melanie creators_name: Piorońska, Weronika creators_name: Sitek, Barbara creators_name: Ebert, Matthias P. creators_name: Hofmann, Ute creators_name: Sleeman, Jonathan creators_name: Wölfl, Stefan creators_name: Meyer, Christoph creators_name: Megger, Dominik A. creators_name: Dooley, Steven title: Liver cancer cell lines distinctly mimic the metabolic gene expression pattern of the corresponding human tumours subjects: 610 divisions: 160100 divisions: 63600 abstract: Background: Although 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. Methods: We 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. Results: We 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. Conclusions: We 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. - - - - - - - - - CORRECTION Published online 2.11.2018 in Journal of Experimental & Clinical Cancer Research, 37 (2018), Nr. 267; DOI: https://doi.org/10.1186/s13046-018-0939-4. In the publication of this article, there was an error in Fig. 5b. This has been updated in the original article on BioMed Central's website. The authors declare that the correction does not change the results or conclusions of this paper. date: 2018 publisher: BioMed Central id_scheme: DOI ppn_swb: 1657209423 own_urn: urn:nbn:de:bsz:16-heidok-254606 language: eng bibsort: NWOSUZERIBLIVERCANCE2018 full_text_status: public publication: Journal of Experimental & Clinical Cancer Research volume: 37 number: 211 place_of_pub: London pagerange: 1-15 issn: 1756-9966 citation: Nwosu, Zeribe C. ; Battello, Nadia ; Rothley, Melanie ; Piorońska, Weronika ; Sitek, Barbara ; Ebert, Matthias P. ; Hofmann, Ute ; Sleeman, Jonathan ; Wölfl, Stefan ; Meyer, Christoph ; Megger, Dominik A. ; Dooley, Steven (2018) Liver cancer cell lines distinctly mimic the metabolic gene expression pattern of the corresponding human tumours. Journal of Experimental & Clinical Cancer Research, 37 (211). pp. 1-15. ISSN 1756-9966 document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/25460/13/13046_2018_Article_872_corrected_version.pdf document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/25460/7/13046_2018_Article_939.pdf