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

doi:10.1194/jlr.M080879

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

Physiology

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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 language	English
Pages (from-to)	795-804
Number of pages	10
Journal	Journal of Lipid Research
Volume	59
Issue number	5
DOIs	https://doi.org/10.1194/jlr.M080879
State	Published - 2018

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grants R01AG034389 and R01NS095215 (E.B.) and American Lung Association Grant RG-351396 (G.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors do not claim any conflicts of interest.

Funding Information:
This work was supported by National Institutes of Health Grants R01AG034389 and R01NS095215 (E.B.) and American Lung Association Grant RG-351396 (G.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors do not claim any conflicts of interest. Manuscript received 25 September 2017 and in revised form 26 February 2018. Published, JLR Papers in Press, March 22, 2018 DOI https://doi.org/10.1194/jlr.M080879

Publisher Copyright:
Copyright © 2018 by the American Society for Biochemistry and Molecular Biology, Inc.

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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@article{b9b095d969914217b32c695b5df0eb8a,

title = "Increased liver tumor formation in neutral sphingomyelinase-2-deficient mice",

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.",

keywords = "Cancer stem-like cells, Ceramide, Ceramide synthase 5, Lipid, Lipido-mics, Sphingolipids, Sphingomyelin, Sphingomyelin phosphodiesterase 3",

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

note = "Funding Information: This work was supported by National Institutes of Health Grants R01AG034389 and R01NS095215 (E.B.) and American Lung Association Grant RG-351396 (G.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors do not claim any conflicts of interest. Funding Information: This work was supported by National Institutes of Health Grants R01AG034389 and R01NS095215 (E.B.) and American Lung Association Grant RG-351396 (G.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors do not claim any conflicts of interest. Manuscript received 25 September 2017 and in revised form 26 February 2018. Published, JLR Papers in Press, March 22, 2018 DOI https://doi.org/10.1194/jlr.M080879 Publisher Copyright: Copyright {\textcopyright} 2018 by the American Society for Biochemistry and Molecular Biology, Inc.",

year = "2018",

doi = "10.1194/jlr.M080879",

language = "English",

volume = "59",

pages = "795--804",

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T1 - Increased liver tumor formation in neutral sphingomyelinase-2-deficient mice

AU - Zhong, Liansheng

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

N1 - Funding Information: This work was supported by National Institutes of Health Grants R01AG034389 and R01NS095215 (E.B.) and American Lung Association Grant RG-351396 (G.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors do not claim any conflicts of interest. Funding Information: This work was supported by National Institutes of Health Grants R01AG034389 and R01NS095215 (E.B.) and American Lung Association Grant RG-351396 (G.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors do not claim any conflicts of interest. Manuscript received 25 September 2017 and in revised form 26 February 2018. Published, JLR Papers in Press, March 22, 2018 DOI https://doi.org/10.1194/jlr.M080879 Publisher Copyright: Copyright © 2018 by the American Society for Biochemistry and Molecular Biology, Inc.

PY - 2018

Y1 - 2018

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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KW - Ceramide synthase 5

KW - Lipid

KW - Lipido-mics

KW - Sphingolipids

KW - Sphingomyelin

KW - Sphingomyelin phosphodiesterase 3

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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