Comparative membrane lipidomics of hepatocellular carcinoma cells reveals diacylglycerol and ceramide as key regulators of Wnt/β‐catenin signaling and tumor growth
Hepatocellular carcinoma (HCC) is largely associated with aberrant activation of Wnt/β‐catenin signaling. Nevertheless, how membrane lipid composition is altered in HCC cells with abnormal Wnt signaling remains elusive. Here, by exploiting comprehensive lipidome profiling, we unravel the membrane li...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-11-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13520 |
| _version_ | 1797642606922956800 |
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| author | Yagmur Azbazdar Yeliz Demirci Guillaume Heger Dogac Ipekgil Mustafa Karabicici Gunes Ozhan |
| author_facet | Yagmur Azbazdar Yeliz Demirci Guillaume Heger Dogac Ipekgil Mustafa Karabicici Gunes Ozhan |
| author_sort | Yagmur Azbazdar |
| collection | DOAJ |
| description | Hepatocellular carcinoma (HCC) is largely associated with aberrant activation of Wnt/β‐catenin signaling. Nevertheless, how membrane lipid composition is altered in HCC cells with abnormal Wnt signaling remains elusive. Here, by exploiting comprehensive lipidome profiling, we unravel the membrane lipid composition of six different HCC cell lines with mutations in components of Wnt/β‐catenin signaling, leading to differences in their endogenous signaling activity. Among the differentially regulated lipids are diacylglycerol (DAG) and ceramide, which were downregulated at the membrane of HCC cells after Wnt3a treatment. DAG and ceramide enhanced Wnt/β‐catenin signaling by inducing caveolin‐mediated endocytosis of the canonical Wnt‐receptor complex, while their depletion suppressed the signaling activity along with a reduction of caveolin‐mediated endocytosis in SNU475 and HepG2 cells. Moreover, depletion of DAG and ceramide significantly impeded the proliferation, tumor growth, and in vivo migration capacity of SNU475 and HepG2 cells. This study, by pioneering plasma membrane lipidome profiling in HCC cells, exhibits the remarkable potential of lipids to correct dysregulated signaling pathways in cancer and stop abnormal tumor growth. |
| first_indexed | 2024-03-11T14:02:50Z |
| format | Article |
| id | doaj.art-dc7455d2e5cf49aca3967751b573d907 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-03-11T14:02:50Z |
| publishDate | 2023-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-dc7455d2e5cf49aca3967751b573d9072023-11-02T04:03:00ZengWileyMolecular Oncology1574-78911878-02612023-11-0117112314233610.1002/1878-0261.13520Comparative membrane lipidomics of hepatocellular carcinoma cells reveals diacylglycerol and ceramide as key regulators of Wnt/β‐catenin signaling and tumor growthYagmur Azbazdar0Yeliz Demirci1Guillaume Heger2Dogac Ipekgil3Mustafa Karabicici4Gunes Ozhan5Izmir Biomedicine and Genome Center (IBG) Dokuz Eylul University Health Campus Izmir TurkeyIzmir Biomedicine and Genome Center (IBG) Dokuz Eylul University Health Campus Izmir TurkeyÉcole Centrale de Nantes FranceIzmir Biomedicine and Genome Center (IBG) Dokuz Eylul University Health Campus Izmir TurkeyIzmir Biomedicine and Genome Center (IBG) Dokuz Eylul University Health Campus Izmir TurkeyIzmir Biomedicine and Genome Center (IBG) Dokuz Eylul University Health Campus Izmir TurkeyHepatocellular carcinoma (HCC) is largely associated with aberrant activation of Wnt/β‐catenin signaling. Nevertheless, how membrane lipid composition is altered in HCC cells with abnormal Wnt signaling remains elusive. Here, by exploiting comprehensive lipidome profiling, we unravel the membrane lipid composition of six different HCC cell lines with mutations in components of Wnt/β‐catenin signaling, leading to differences in their endogenous signaling activity. Among the differentially regulated lipids are diacylglycerol (DAG) and ceramide, which were downregulated at the membrane of HCC cells after Wnt3a treatment. DAG and ceramide enhanced Wnt/β‐catenin signaling by inducing caveolin‐mediated endocytosis of the canonical Wnt‐receptor complex, while their depletion suppressed the signaling activity along with a reduction of caveolin‐mediated endocytosis in SNU475 and HepG2 cells. Moreover, depletion of DAG and ceramide significantly impeded the proliferation, tumor growth, and in vivo migration capacity of SNU475 and HepG2 cells. This study, by pioneering plasma membrane lipidome profiling in HCC cells, exhibits the remarkable potential of lipids to correct dysregulated signaling pathways in cancer and stop abnormal tumor growth.https://doi.org/10.1002/1878-0261.13520ceramidecomparative lipidome profilingdiacylglycerolhepatocellular carcinomaplasma membraneWnt/β‐catenin pathway |
| spellingShingle | Yagmur Azbazdar Yeliz Demirci Guillaume Heger Dogac Ipekgil Mustafa Karabicici Gunes Ozhan Comparative membrane lipidomics of hepatocellular carcinoma cells reveals diacylglycerol and ceramide as key regulators of Wnt/β‐catenin signaling and tumor growth Molecular Oncology ceramide comparative lipidome profiling diacylglycerol hepatocellular carcinoma plasma membrane Wnt/β‐catenin pathway |
| title | Comparative membrane lipidomics of hepatocellular carcinoma cells reveals diacylglycerol and ceramide as key regulators of Wnt/β‐catenin signaling and tumor growth |
| title_full | Comparative membrane lipidomics of hepatocellular carcinoma cells reveals diacylglycerol and ceramide as key regulators of Wnt/β‐catenin signaling and tumor growth |
| title_fullStr | Comparative membrane lipidomics of hepatocellular carcinoma cells reveals diacylglycerol and ceramide as key regulators of Wnt/β‐catenin signaling and tumor growth |
| title_full_unstemmed | Comparative membrane lipidomics of hepatocellular carcinoma cells reveals diacylglycerol and ceramide as key regulators of Wnt/β‐catenin signaling and tumor growth |
| title_short | Comparative membrane lipidomics of hepatocellular carcinoma cells reveals diacylglycerol and ceramide as key regulators of Wnt/β‐catenin signaling and tumor growth |
| title_sort | comparative membrane lipidomics of hepatocellular carcinoma cells reveals diacylglycerol and ceramide as key regulators of wnt β catenin signaling and tumor growth |
| topic | ceramide comparative lipidome profiling diacylglycerol hepatocellular carcinoma plasma membrane Wnt/β‐catenin pathway |
| url | https://doi.org/10.1002/1878-0261.13520 |
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