Hepatocellular Carcinomas With Mutational Activation of Beta-Catenin Require Choline and Can Be Detected by Positron Emission Tomography

Gougelet, Angélique; Sartor, Chiara; Senni, Nadia; Caldéraro, Julien; Fartoux, Lætitia; Lequoy, Marie; Wendum, Dominique; Talbot, J.-N.; Prignon, Aurélie; Chalaye, Julia; Imbeaud, Sandrine; Zucman‐Rossi, Jessica; Tordjmann, Thierry; Godard, Cécile; Bossard, Pascale; Rosmorduc, Olivier; Amaddeo, Giuliana; Colnot, Sabine

doi:10.1053/j.gastro.2019.05.069

Cited by 27 publications

(39 citation statements)

References 36 publications

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“…The phospholipid signatures that best discriminated HCC from non-tumor liver tissue in our study included several different species of phosphatidylcholines. PET imaging using 18 F-fluorocholine is an imaging biomarker of phosphotidylcholine synthesis that is currently used for clinical detection of HCC in some regions [43,44] It has been shown to be superior to PET imaging of glucose metabolism with 18 F-fluoro-deoxy-D-glucose (FDG) for the detection of HCC, implying that lipogenesis is more salient than glycolysis as a metabolic feature of HCC [43,45,46]. Other studies have identified lipogenic networks characterized by specific lipid metabolites as being associated with HCC progression and survival [20].…”

Section: Discussionmentioning

confidence: 99%

“…Other studies have identified lipogenic networks characterized by specific lipid metabolites as being associated with HCC progression and survival [20]. The Wnt/beta-catenin pathway has been implicated in hepatocarcinogenesis [47], and mutations causing activation of beta-catenin have been associated with increased tumor phospholipid biosynthesis and uptake of 18 F-fluorocholine in HCC [44]. Beta-catenin activation has also been associated with increased fatty acid oxidation in HCC [48].…”

Section: Discussionmentioning

confidence: 99%

“…Beta-catenin activation has also been associated with increased fatty acid oxidation in HCC [48]. Imaging of lipid metabolism may therefore have the potential to discriminate specific molecular sub-types of HCC [17,44].…”

Section: Discussionmentioning

confidence: 99%

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Phospholipids are A Potentially Important Source of Tissue Biomarkers for Hepatocellular Carcinoma: Results of a Pilot Study Involving Targeted Metabolomics

et al. 2019

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Background: Hepatocellular carcinoma (HCC) pathogenesis involves the alteration of multiple liver-specific metabolic pathways. We systematically profiled cancer-and liver-related classes of metabolites in HCC and adjacent liver tissues and applied supervised machine learning to compare their potential yield for HCC biomarkers. Methods: Tumor and corresponding liver tissue samples were profiled as follows: Bile acids by ultra-performance liquid chromatography (LC) coupled to tandem mass spectrometry (MS), phospholipids by LC-MS/MS, and other small molecules including free fatty acids by gas chromatography-time of flight MS. The overall classification performance of metabolomic signatures derived by support vector machine (SVM) and random forests machine learning algorithms was then compared across classes of metabolite. Results: For each metabolite class, there was a plateau in classification performance with signatures of 10 metabolites. Phospholipid signatures consistently showed the highest discrimination for HCC followed by signatures derived from small molecules, free fatty acids, and bile acids with area under the receiver operating characteristic curve (AUC) values of 0.963, 0.934, 0.895, 0.695, respectively, for SVM-generated signatures comprised of 10 metabolites. Similar classification performance patterns were observed with signatures derived by random forests. Conclusion: Membrane phospholipids are a promising source of tissue biomarkers for discriminating between HCC tumor and liver tissue.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Phospholipids are A Potentially Important Source of Tissue Biomarkers for Hepatocellular Carcinoma: Results of a Pilot Study Involving Targeted Metabolomics

et al. 2019

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“…The dysregulation of β-catenin was involved in HCC progression. Additionally, CTNNB1 mutation was frequently detected in HCC tissues compared to those of adjacent liver (31). The data in this study identified NCSTN as the upstream regulator of βcatenin and promoted its nuclear translocation, thereby induced Zeb1-mediated EMT process, resulting in malignant phenotype.…”

Section: Discussionmentioning

confidence: 60%

NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner

Lan

et al. 2020

Preprint

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Background Hepatocellular carcinoma is the third top cause of cancer-related mortalities worldwide. The prognosis of HCC patients remains poor due to rapid progression and high incidence of tumor recurrence. Nicastrin (NCSTN), a core subunit of γ-Secretase, has been reported to play a vital role in tumor progression. However, no study till now has revealed its role in HCC. Methods The expression of NCSTN was evaluated by immunohistochemical staining, Western blot, and quantitative real-time PCR. Cell counting kit-8, colony formation and cell cycle assays were used for evaluating cell growth in vitro. Transwell and wound-healing assays were used for evaluating cell migration and invasion capacity. Immunofluorescence, subcellular protein fractionation and co-immunoprecipitation were used for location analysis of β-catenin. The in vivo functions of NCSTN were illustrated by xenograft tumor models. Results NCSTN was dramatically overexpressed in HCC compared to normal liver tissues. Elevated NCSTN expression level was significantly correlated to worse overall and recurrence-free survival of HCC patients. Enhanced NCSTN expression promoted HCC cell growth, migration and invasion in vitro and in vivo. Mechanistic investigations showed that NCSTN induced epithelial-mesenchymal transition (EMT) process via upregulation of Zeb1. Subsequently, we revealed that NCSTN facilitated nuclear translocation of β-catenin, a positive transcriptional regulator of Zeb1. Using Notch and AKT inhibitors, we revealed that NCSTN promoted β-catenin activation through Notch1 and AKT signaling pathway. NCSTN increased AKT and GSK-3β phosphorylation by cleavage of Notch1, which decreased GSK-3β/β-catenin complex. The inactivation of GSK-3β inhibited the β-catenin degradation and promoted nuclear translocation of β-catenin to initiate transcription of Zeb1, resulting in malignant phenotype. Conclusions Our results demonstrated that NCSTN promoted HCC cell growth and metastasis via β-catenin-mediated upregulation of Zeb1 in a Notch1/AKT dependent manner, suggesting that NCSTN might serve as a potential prognostic marker and therapeutic target for HCC.

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“…Additionally, the focal activation of β-catenin in vivo in single murine hepatocytes is oncogenic, leading to the development of β-catenin-activated liver tumors ( Colnot et al, 2004 ). We used transcriptomic and metabolomic approaches and showed that the genetic program expressed in β-catenin-activated liver is similar to the oncogenic signature found in human HCC harboring activating β-catenin mutations ( Gougelet et al, 2014 ; Gougelet et al, 2019 ; Senni et al, 2019 ).…”

Section: Introductionmentioning

confidence: 96%

ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription

Riou

Ladli

Gerbal‐Chaloin

et al. 2020

eLife

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Erythropoietin (EPO) is a key regulator of erythropoiesis. The embryonic liver is the main site of erythropoietin synthesis, after which the kidney takes over. The adult liver retains the ability to express EPO, and we discovered here new players of this transcription, distinct from the classical hypoxia-inducible factor pathway. In mice genetically-invalidated in hepatocytes for the chromatin remodeler Arid1a, and for Apc, the major silencer of Wnt pathway, chromatin was more accessible and histone marks turned into active ones at the Epo downstream enhancer. Activating β-catenin signaling increased binding of Tcf4/β-catenin complex and upregulated its enhancer function. The loss of Arid1a together with β-catenin signaling, resulted in cell-autonomous EPO transcription in mouse and human hepatocytes. In mice with Apc-Arid1a gene invalidations in single hepatocytes, Epo de novo synthesis led to its secretion, to splenic erythropoiesis and to dramatic erythrocytosis. Thus, we identified new hepatic EPO regulation mechanism stimulating erythropoiesis.

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Hepatocellular Carcinomas With Mutational Activation of Beta-Catenin Require Choline and Can Be Detected by Positron Emission Tomography

Cited by 27 publications

References 36 publications

Phospholipids are A Potentially Important Source of Tissue Biomarkers for Hepatocellular Carcinoma: Results of a Pilot Study Involving Targeted Metabolomics

Phospholipids are A Potentially Important Source of Tissue Biomarkers for Hepatocellular Carcinoma: Results of a Pilot Study Involving Targeted Metabolomics

NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner

ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription

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