Deletion of sphingosine kinase 1 inhibits liver tumorigenesis in diethylnitrosamine-treated mice.
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.
['Chen|Jinbiao|J|', 'Qi|Yanfei|Y|', 'Zhao|Yang|Y|', 'Kaczorowski|Dominik|D|', 'Couttas|Timothy A|TA|', 'Coleman|Paul R|PR|', 'Don|Anthony S|AS|', 'Bertolino|Patrick|P|', 'Gamble|Jennifer R|JR|', 'Vadas|Mathew A|MA|', 'Xia|Pu|P|', 'McCaughan|Geoffrey W|GW|']
sphingosine liver cancer Sphk1 mouse myc