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

Liansheng Zhong, Ji Na Kong, Michael B. Dinkins, Silvia Leanhart, Zhihui Zhu, Stefka D. Spassieva, Haiyan Qin, Hsuan Pei Lin, Ahmed Elsherbini, Rebecca Wang, Xue Jiang, Mariana Nikolova-Karakashian, Guanghu Wang, Erhard Bieberich

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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 C 16 -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.

Original languageEnglish (US)
Pages (from-to)795-804
Number of pages10
JournalJournal of Lipid Research
Volume59
Issue number5
DOIs
StatePublished - Jan 1 2018

Fingerprint

Sphingomyelin Phosphodiesterase
Liver
Tumors
Neoplasms
Lipids
Sphingolipids
Ceramides
Neoplastic Stem Cells
Tissue
STAT3 Transcription Factor
Liver Neoplasms
Growth
Labeling
Hepatocellular Carcinoma
Genes
Homeostasis
Up-Regulation

Keywords

  • Cancer stem-like cells
  • Ceramide
  • Ceramide synthase 5
  • Lipid
  • Lipido-mics
  • Sphingolipids
  • Sphingomyelin
  • Sphingomyelin phosphodiesterase 3

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Zhong, L., Kong, J. N., Dinkins, M. B., Leanhart, S., Zhu, Z., Spassieva, S. D., ... Bieberich, E. (2018). Increased liver tumor formation in neutral sphingomyelinase-2-deficient mice. Journal of Lipid Research, 59(5), 795-804. https://doi.org/10.1194/jlr.M080879

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

In: Journal of Lipid Research, Vol. 59, No. 5, 01.01.2018, p. 795-804.

Research output: Contribution to journalArticle

Zhong, L, Kong, JN, Dinkins, MB, Leanhart, S, Zhu, Z, Spassieva, SD, Qin, H, Lin, HP, Elsherbini, A, Wang, R, Jiang, X, Nikolova-Karakashian, M, Wang, G & Bieberich, E 2018, 'Increased liver tumor formation in neutral sphingomyelinase-2-deficient mice', Journal of Lipid Research, vol. 59, no. 5, pp. 795-804. https://doi.org/10.1194/jlr.M080879
Zhong L, Kong JN, Dinkins MB, Leanhart S, Zhu Z, Spassieva SD et al. Increased liver tumor formation in neutral sphingomyelinase-2-deficient mice. Journal of Lipid Research. 2018 Jan 1;59(5):795-804. https://doi.org/10.1194/jlr.M080879
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. / Increased liver tumor formation in neutral sphingomyelinase-2-deficient mice. In: Journal of Lipid Research. 2018 ; Vol. 59, No. 5. pp. 795-804.
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abstract = "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 C 16 -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.",
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AU - Kong, Ji Na

AU - Dinkins, Michael B.

AU - Leanhart, Silvia

AU - Zhu, Zhihui

AU - Spassieva, Stefka D.

AU - Qin, Haiyan

AU - Lin, Hsuan Pei

AU - Elsherbini, Ahmed

AU - Wang, Rebecca

AU - Jiang, Xue

AU - Nikolova-Karakashian, Mariana

AU - Wang, Guanghu

AU - Bieberich, Erhard

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N2 - 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 C 16 -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.

AB - 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 C 16 -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.

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