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Increased liver tumor formation in neutral sphingomyelinase-2-deficient mice
Liansheng Zhong1,2, Ji Na Kong3, Michael B Dinkins4
1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY.
Abstract:
Sphingolipids are key signaling lipids in cancer. Genome-wide studies have identified neutral SMase-2 (nSMase2), an enzyme generating ceramide from SM, as a potential repressor for hepatocellular carcinoma. However, little is known about the sphingolipids regulated by nSMase2 and their roles in liver tumor development. We discovered growth of spontaneous liver tumors in 27.3% (9 of 33) of aged male nSMase2-deficient (fro/fro) mice. Lipidomics analysis showed a marked increase of SM in the tumor. Unexpectedly, tumor tissues presented with more than a 7-fold increase of C16-ceramide, concurrent with upregulation of ceramide synthase 5. The fro/fro liver tumor, but not adjacent tissue, exhibited substantial accumulation of lipid droplets, suggesting that nSMase2 deficiency is associated with tumor growth and increased neutral lipid generation in the tumor. Tumor tissue expressed significantly increased levels of CD133 and EpCAM mRNA, two markers of liver cancer stem-like cells (CSCs) and higher levels of phosphorylated signal transducer and activator of transcription 3, an essential regulator of stemness. CD133(+) cells showed strong labeling for SM and ceramide. In conclusion, these results suggest that SMase-2 deficiency plays a role in the survival or proliferation of CSCs, leading to spontaneous tumors, which is associated with tumor-specific effects on lipid homeostasis.
Insights
Neutral sphingomyelinase-2 (nSMase2) deficiency promotes spontaneous liver tumors in mice. This is linked to increased ceramide, lipid droplets, and cancer stem cells, impacting liver tumor development and lipid homeostasis.
Area of Science:
- Biochemistry
- Oncology
- Lipid Metabolism
Background:
- Sphingolipids are crucial signaling molecules in cancer development.
- Neutral sphingomyelinase-2 (nSMase2) is implicated as a hepatocellular carcinoma suppressor.
- The precise role of nSMase2-regulated sphingolipids in liver tumorigenesis remains unclear.
Purpose of the Study:
- To investigate the role of nSMase2 in liver tumor development.
- To identify sphingolipids regulated by nSMase2 and their impact on liver cancer.
- To explore the association between nSMase2 deficiency, cancer stem cells, and lipid metabolism in liver tumors.
Main Methods:
- Utilized nSMase2-deficient (fro/fro) mice to study spontaneous liver tumor formation.
- Performed lipidomics analysis to quantify sphingolipid levels in tumor tissues.
- Assessed the expression of liver cancer stem cell markers (CD133, EpCAM) and signaling pathways (pSTAT3).
Main Results:
- nSMase2-deficient mice developed spontaneous liver tumors with increased sphingomyelin (SM) and C16-ceramide levels.
- Tumor tissues showed elevated ceramide synthase 5, substantial lipid droplet accumulation, and increased CD133 and EpCAM mRNA.
- CD133-positive cells exhibited high SM and ceramide labeling, alongside increased phosphorylated signal transducer and activator of transcription 3 (pSTAT3).
Conclusions:
- nSMase2 deficiency contributes to spontaneous liver tumor growth.
- This deficiency is associated with altered lipid homeostasis, including increased neutral lipids and specific ceramides.
- nSMase2 may play a role in the survival and proliferation of liver cancer stem cells, driving tumor development.
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