Hepatotoxin-induced changes in the adult murine liver promote MYC-induced tumorigenesis.
BACKGROUND
Overexpression of the human c-MYC (MYC) oncogene is one of the most frequently implicated events in the pathogenesis of hepatocellular carcinoma (HCC). Previously, we have shown in a conditional transgenic mouse model that MYC overexpression is restrained from inducing mitotic cellular division and tumorigenesis in the adult liver; whereas, in marked contrast, MYC induces robust proliferation associated with the very rapid onset of tumorigenesis in embryonic and neonatal mice.


RESULTS
Here, we show that non-genotoxic hepatotoxins induce changes in the liver cellular context associated with increased cellular proliferation and enhanced tumorigenesis. Both 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride (CCl(4)) cooperate with MYC to greatly accelerate the onset of liver cancer in an adult host to less than 7 days versus a mean latency of onset of over 35 weeks for MYC alone. These hepatotoxin-enhanced liver tumors grossly and histologically resemble embryonic and neonatal liver tumors. Importantly, we found that MYC overexpression is only capable of inducing expression of the mitotic Cyclin B1 in embryonic/neonatal hosts or adult hosts that were treated with either carcinogen.


CONCLUSIONS
Our results suggest a model whereby oncogenes can remain latently activated, but exposure of the adult liver to hepatotoxins that promote hepatocyte proliferation can rapidly uncover their malignant potential.
Department of Medicine, Division of Oncology, School of Medicine, Center for Clinical Sciences Research, Stanford University, Stanford, California, United States of America.
Shelly
S
Beer
Kimberly
K
Komatsubara
David I
DI
Bellovin
Masashi
M
Kurobe
Karl
K
Sylvester
Dean W
DW
Felsher
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D017931:DNA Primers; D003997:Dicarbethoxydihydrocollidine / Q000633:toxicity*; D016259:Genes, myc; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D011725:Pyridines / Q000633:toxicity*
C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; D002273:Carcinogens; D017931:DNA Primers; D011725:Pyridines; D003997:Dicarbethoxydihydrocollidine; D002251:Carbon Tetrachloride