Increased liver tumor formation in neutral sphingomyelinase-2-deficient mice

• Published in: Journal of lipid research Vol. 59; no. 5; pp. 795 - 804
• Main Authors: Zhong, Liansheng, Kong, Ji Na, Dinkins, Michael B., Leanhart, Silvia, Zhu, Zhihui, Spassieva, Stefka D., Qin, Haiyan, Lin, Hsuan-Pei, Elsherbini, Ahmed, Wang, Rebecca, Jiang, Xue, Nikolova-Karakashian, Mariana, Wang, Guanghu, Bieberich, Erhard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2018; Journal of Lipid Research; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Animals; cancer stem-like cells; Cell Proliferation; Ceramide; ceramide synthase 5; Genomes; Hepatocellular carcinoma; Hepatocytes; Homeostasis; lipid; lipidomics; Lipids; Liver cancer; Liver Neoplasms - enzymology; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Male; Mice; Mice, Knockout; Sphingolipids; sphingomyelin; Sphingomyelin phosphodiesterase; Sphingomyelin Phosphodiesterase - deficiency; Sphingomyelin Phosphodiesterase - genetics; sphingomyelin phosphodiesterase 3; Transcription; Tumors; sphingomyelin phosphodiesterase 3; ceramide; cancer stem-like cells; ceramide synthase 5; sphingolipids; sphingomyelin; lipid; lipidomics
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M080879

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.