Oncotarget

Research Papers:

Deletion of sphingosine kinase 1 inhibits liver tumorigenesis in diethylnitrosamine-treated mice

Jinbiao Chen, Yanfei Qi, Yang Zhao, Dominik Kaczorowski, Timothy A. Couttas, Paul R. Coleman, Anthony S. Don, Patrick Bertolino, Jennifer R. Gamble, Mathew A. Vadas, Pu Xia and Geoffrey W. McCaughan _

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Oncotarget. 2018; 9:15635-15649. https://doi.org/10.18632/oncotarget.24583

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Abstract

Jinbiao Chen1,7, Yanfei Qi2, Yang Zhao2, Dominik Kaczorowski1, Timothy A. Couttas3, Paul R. Coleman2, Anthony S. Don3, Patrick Bertolino4, Jennifer R. Gamble2,*, Mathew A. Vadas2,*, Pu Xia5,* and Geoffrey W. McCaughan1,6,7,*

1Liver Injury and Cancer, Camperdown, NSW 2050, Australia

2Vascular Biology, Camperdown, NSW 2050, Australia

3ACRF Centenary Cancer Research, Camperdown, NSW 2050, Australia

4Liver Immunology in Centenary Institute, Camperdown, NSW 2050, Australia

5Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200032, China

6A.W. Morrow Gastroenterology and Liver Center, Australian Liver Transplant Unit, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia

7Sydney Medical School, University of Sydney, Camperdown, NSW 2050, Australia

*These authors contributed equally to this work

Correspondence to:

Geoffrey W. McCaughan, email: g.mccaughan@centenary.usyd.edu.au

Pu Xia, email: xiapu_fudan@163.com

Keywords: mouse; liver cancer; Sphk1; sphingosine; myc

Abbreviations: SphK: sphingosine kinase

Received: December 13, 2017     Accepted: February 21, 2018     Epub: February 26, 2018     Published: March 20, 2018

ABSTRACT

Primary liver cancer is the 3rd leading cause of cancer deaths worldwide with very few effective treatments. Sphingosine kinase 1 (SphK1), a key regulator of sphingolipid metabolites, is over-expressed in human hepatocellular carcinoma (HCC) and our previous studies have shown that SphK1 is important in liver injury. We aimed to explore the role of SphK1 specifically in liver tumorigenesis using the SphK1 knockout (SphK1−/−) mouse. SphK1 deletion significantly reduced the number and the size of DEN-induced liver cancers in mice. Mechanistically, fewer proliferating but more apoptotic and senescent cells were detected in SphK1 deficient tumors compared to WT tumors. There was an increase in sphingosine rather than a decrease in sphingosine 1-phosphate (S1P) in SphK1 deficient tumors. Furthermore, the STAT3-S1PR pathway that has been reported previously to mediate the effect of SphK1 on colorectal cancers was not altered by SphK1 deletion in liver cancer. Instead, c-Myc protein expression was down-regulated by SphK1 deletion. In conclusion, this is the first in vivo evidence that SphK1 contributes to hepatocarcinogenesis. However, the downstream signaling pathways impacting on the development of HCC via SphK1 are organ specific providing further evidence that simply transferring known oncogenic molecular pathway targeting into HCC is not always valid.


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