Genomic Profiling and Metabolic Homeostasis in Primary Liver Cancers

Gingold, Julian A.; Zhu, Dandan; Lee, Dung‐Fang; Kaseb, Ahmed O.; Chen, Jian

doi:10.1016/j.molmed.2018.02.006

Cited by 53 publications

(37 citation statements)

References 113 publications

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“…Recent studies have provided evidence of profound metabolic alterations in human liver cancer [13, 28–33]. HCC cell lines are among a plethora of preclinical experimental models (e.g.…”

Section: Discussionmentioning

confidence: 99%

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

Nwosu

Battello²,

Rothley

et al. 2018

J Exp Clin Cancer Res

104

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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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“…Recent studies have provided evidence of profound metabolic alterations in human liver cancer [13, 28–33]. HCC cell lines are among a plethora of preclinical experimental models (e.g.…”

Section: Discussionmentioning

confidence: 99%

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

Nwosu

Battello²,

Rothley

et al. 2018

J Exp Clin Cancer Res

104

View full text Add to dashboard Cite

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“…Although the frequency and type of genomic alteration in the TGF-b superfamily varied widely across tumor types, alterations affecting TGF-b signaling were most common in gastrointestinal cancers, including colorectal, esophageal/stomach, pancreatic, and liver. The most common somatic mutations in HCC were summarized and reviewed recently [33,34].…”

Section: Genomic Alterations In the Tgf-b Superfamily In Hccmentioning

confidence: 99%

Immunomodulatory TGF-β Signaling in Hepatocellular Carcinoma

Chen

Gingold

2019

Trends in Molecular Medicine

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183

135

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Hepatocellular carcinoma (HCC) is an inflammation-induced and chemotherapy-resistant cancer. Dysregulated signaling in the transforming growth factor beta (TGF-b) pathway plays a central role in inflammation, fibrogenesis, and immunomodulation in the HCC microenvironment. This review dissects the genetic landscape of the TGF-b superfamily genes in HCC and discusses the essential effects of this pathway on the tumor immune microenvironment. We highlight the TGF-b signature as a potential biomarker for identifying individualized immunotherapeutic approaches in HCC. An improved understanding of the detailed mechanisms of liver cancer immunogenicity and the specific role of TGF-b in mediating immunotherapy resistance in HCC will provide important insights into HCC immune escape and promote the development of biomarker-derived combination immunotherapies for HCC.

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“…Persisting chronic liver injury induces a continuous cycle of inflammation, regeneration and proliferation of hepatocytes that results in accumulation of pathophysiologic aberrancies that lead to fibrosis, cirrhosis, and HCC initiation, as discussed above in detail [95]. However, 20% of patients with HBV develop HCC without evident cirrhosis [96].…”

Section: Prognostic and Diagnostic Cytokine Biomarkers In Hcc Patientmentioning

confidence: 99%

Origin and role of hepatic myofibroblasts in hepatocellular carcinoma

et al. 2020

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Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the second leading cause of cancer-related death worldwide. Fibrosis and cirrhosis are important risk factors for the development of HCC. Hepatic myofibroblasts are the cells responsible for extracellular matrix deposition, which is the hallmark of liver fibrosis. It is believed that myofibroblasts are predominantly derived from hepatic stellate cells (HSCs), also known as Ito cells. Nevertheless, depending on the nature of insult to the liver, it is thought that myofibroblasts may also originate from a variety of other cell types such as the portal fibroblasts (PFs), fibrocytes, hepatocytes, hepatic progenitor cells (HPCs), and mesothelial cells. Liver myofibroblasts are believed to transform into cancer-associated fibroblasts (CAFs) while HCC is developing. There is substantial evidence suggesting that activated HSCs (aHSCs)/cancer-associated fibroblasts (CAFs) may play an important role in HCC initiation and progression. In this paper, we aim to review current literature on cellular origins of myofibroblasts with a focus on hepatitis B virus (HBV)-and hepatitis C virus (HCV)-induced hepatic fibrosis. We also address the role of aHSCs/CAFs in HCC progression through the regulation of immune cells as well as mechanisms of evolvement of drug resistance.

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Genomic Profiling and Metabolic Homeostasis in Primary Liver Cancers

Cited by 53 publications

References 113 publications

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

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

Immunomodulatory TGF-β Signaling in Hepatocellular Carcinoma

Origin and role of hepatic myofibroblasts in hepatocellular carcinoma

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