Ablation of sphingosine kinase 2 suppresses fatty liver-associated hepatocellular carcinoma via downregulation of ceramide transfer protein
Abstract Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer, the third leading cause of cancer-associated death worldwide. With the increasing prevalence of metabolic conditions, non-alcoholic fatty liver disease (NAFLD) is emerging as the fastest-growing HCC risk factor, and it...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-11-01
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| Series: | Oncogenesis |
| Online Access: | https://doi.org/10.1038/s41389-022-00444-0 |
| _version_ | 1797984617166274560 |
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| author | Xin Tracy Liu Long Hoa Chung Da Liu Jinbiao Chen Yu Huang Jonathan D. Teo Xingxing Daisy Han Yinan Zhao Fiona H. X. Guan Collin Tran Jun Yup Lee Timothy A. Couttas Ken Liu Geoffery W. McCaughan Mark D. Gorrell Anthony S. Don Shubiao Zhang Yanfei Qi |
| author_facet | Xin Tracy Liu Long Hoa Chung Da Liu Jinbiao Chen Yu Huang Jonathan D. Teo Xingxing Daisy Han Yinan Zhao Fiona H. X. Guan Collin Tran Jun Yup Lee Timothy A. Couttas Ken Liu Geoffery W. McCaughan Mark D. Gorrell Anthony S. Don Shubiao Zhang Yanfei Qi |
| author_sort | Xin Tracy Liu |
| collection | DOAJ |
| description | Abstract Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer, the third leading cause of cancer-associated death worldwide. With the increasing prevalence of metabolic conditions, non-alcoholic fatty liver disease (NAFLD) is emerging as the fastest-growing HCC risk factor, and it imposes an additional layer of difficulty in HCC management. Dysregulated hepatic lipids are generally believed to constitute a deleterious environment cultivating the development of NAFLD-associated HCC. However, exactly which lipids or lipid regulators drive this process remains elusive. We report herein that sphingosine kinase 2 (SphK2), a key sphingolipid metabolic enzyme, plays a critical role in NAFLD-associated HCC. Ablation of Sphk2 suppressed HCC development in NAFLD livers via inhibition of hepatocyte proliferation both in vivo and in vitro. Mechanistically, SphK2 deficiency led to downregulation of ceramide transfer protein (CERT) that, in turn, decreased the ratio of pro-cancer sphingomyelin (SM) to anti-cancer ceramide. Overexpression of CERT restored hepatocyte proliferation, colony growth and cell cycle progression. In conclusion, the current study demonstrates that SphK2 is an essential lipid regulator in NAFLD-associated HCC, providing experimental evidence to support clinical trials of SphK2 inhibitors as systemic therapies against HCC. |
| first_indexed | 2024-04-11T07:04:25Z |
| format | Article |
| id | doaj.art-7334783c3e6f40f3a030ad5e6b012c91 |
| institution | Directory Open Access Journal |
| issn | 2157-9024 |
| language | English |
| last_indexed | 2024-04-11T07:04:25Z |
| publishDate | 2022-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Oncogenesis |
| spelling | doaj.art-7334783c3e6f40f3a030ad5e6b012c912022-12-22T04:38:25ZengNature Publishing GroupOncogenesis2157-90242022-11-0111111210.1038/s41389-022-00444-0Ablation of sphingosine kinase 2 suppresses fatty liver-associated hepatocellular carcinoma via downregulation of ceramide transfer proteinXin Tracy Liu0Long Hoa Chung1Da Liu2Jinbiao Chen3Yu Huang4Jonathan D. Teo5Xingxing Daisy Han6Yinan Zhao7Fiona H. X. Guan8Collin Tran9Jun Yup Lee10Timothy A. Couttas11Ken Liu12Geoffery W. McCaughan13Mark D. Gorrell14Anthony S. Don15Shubiao Zhang16Yanfei Qi17Centenary Institute, The University of SydneyCentenary Institute, The University of SydneyCentenary Institute, The University of SydneyCentenary Institute, The University of SydneyCentenary Institute, The University of SydneySchool of Medical Sciences and Charles Perkins Centre, Faculty of Medicine and Health, University of SydneyCentenary Institute, The University of SydneyKey Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu UniversityAW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney Local Health DistrictSchool of Medical Sciences and Charles Perkins Centre, Faculty of Medicine and Health, University of SydneySchool of Medical Sciences and Charles Perkins Centre, Faculty of Medicine and Health, University of SydneyBrain and Mind Centre, Faculty of Medicine and Health, University of SydneyAW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney Local Health DistrictCentenary Institute, The University of SydneyCentenary Institute, The University of SydneySchool of Medical Sciences and Charles Perkins Centre, Faculty of Medicine and Health, University of SydneyKey Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu UniversityCentenary Institute, The University of SydneyAbstract Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer, the third leading cause of cancer-associated death worldwide. With the increasing prevalence of metabolic conditions, non-alcoholic fatty liver disease (NAFLD) is emerging as the fastest-growing HCC risk factor, and it imposes an additional layer of difficulty in HCC management. Dysregulated hepatic lipids are generally believed to constitute a deleterious environment cultivating the development of NAFLD-associated HCC. However, exactly which lipids or lipid regulators drive this process remains elusive. We report herein that sphingosine kinase 2 (SphK2), a key sphingolipid metabolic enzyme, plays a critical role in NAFLD-associated HCC. Ablation of Sphk2 suppressed HCC development in NAFLD livers via inhibition of hepatocyte proliferation both in vivo and in vitro. Mechanistically, SphK2 deficiency led to downregulation of ceramide transfer protein (CERT) that, in turn, decreased the ratio of pro-cancer sphingomyelin (SM) to anti-cancer ceramide. Overexpression of CERT restored hepatocyte proliferation, colony growth and cell cycle progression. In conclusion, the current study demonstrates that SphK2 is an essential lipid regulator in NAFLD-associated HCC, providing experimental evidence to support clinical trials of SphK2 inhibitors as systemic therapies against HCC.https://doi.org/10.1038/s41389-022-00444-0 |
| spellingShingle | Xin Tracy Liu Long Hoa Chung Da Liu Jinbiao Chen Yu Huang Jonathan D. Teo Xingxing Daisy Han Yinan Zhao Fiona H. X. Guan Collin Tran Jun Yup Lee Timothy A. Couttas Ken Liu Geoffery W. McCaughan Mark D. Gorrell Anthony S. Don Shubiao Zhang Yanfei Qi Ablation of sphingosine kinase 2 suppresses fatty liver-associated hepatocellular carcinoma via downregulation of ceramide transfer protein Oncogenesis |
| title | Ablation of sphingosine kinase 2 suppresses fatty liver-associated hepatocellular carcinoma via downregulation of ceramide transfer protein |
| title_full | Ablation of sphingosine kinase 2 suppresses fatty liver-associated hepatocellular carcinoma via downregulation of ceramide transfer protein |
| title_fullStr | Ablation of sphingosine kinase 2 suppresses fatty liver-associated hepatocellular carcinoma via downregulation of ceramide transfer protein |
| title_full_unstemmed | Ablation of sphingosine kinase 2 suppresses fatty liver-associated hepatocellular carcinoma via downregulation of ceramide transfer protein |
| title_short | Ablation of sphingosine kinase 2 suppresses fatty liver-associated hepatocellular carcinoma via downregulation of ceramide transfer protein |
| title_sort | ablation of sphingosine kinase 2 suppresses fatty liver associated hepatocellular carcinoma via downregulation of ceramide transfer protein |
| url | https://doi.org/10.1038/s41389-022-00444-0 |
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