The v-raf oncogene enhances tumorigenicity and suppresses differentiation in vivo in a rat hepatocyte cell line.
raf oncogenes have been implicated in hepatic carcinogenesis. We studied the effects of the v-raf of murine retrovirus 3611-MSV on the growth and differentiation of a simian virus 40 (SV40)-immortalized rat liver cell line (ALB-8) which maintained many of characteristics of differentiated hepatocytes. Cells were co-transfected with v-raf and the neo gene followed by selection with G418 for transfectants. In culture, the expression of v-raf stimulated cell proliferation without altering cell morphology or expression of liver-specific genes: albumin, fibrinogen, alpha-1-antitrypsin and alpha-1-acid glycoprotein. The v-raf-transfected cells induced rapidly growing tumors in 100% of nude mice, while control DNA-transfected cells were only weakly tumorigenic, producing slowly growing tumors in 2/7 mice after a long latency. These slowly growing tumors were histologically moderately to well-differentiated hepatocellular carcinomas in which the liver-specific genes were highly expressed. In contrast, v-raf-induced tumors were histologically poorly differentiated and showed a dramatic decline in the expression of the liver-specific genes. In a tumor cell culture established from a v-raf-induced tumor, however, expression of the liver-specific genes was coordinately recovered. These observations indicate that v-raf is capable of inducing progression of SV40-immortalized hepatocytes into highly malignant cells and the progression is accompanied by loss, in vivo, of the hepatic differentiation.
Fang
X J
XJ
Department of Medicine, Toronto Hospital, Ontario, Canada.
Keating
A
A
Flowers
M
M
Liew
C C
CC
Gupta
H
H
Mills
G B
GB
Sherman
M
M
D000418:Albumins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002461:Cell Line, Transformed; D015536:Down-Regulation; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009857:Oncogenes / Q000502:physiology*; D009961:Orosomucoid / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D051381:Rats; D013539:Simian virus 40 / Q000235:genetics; D014162:Transfection; D000515:alpha 1-Antitrypsin / Q000378:metabolism
D000418:Albumins; D009961:Orosomucoid; D012334:RNA, Neoplasm; D000515:alpha 1-Antitrypsin; D012313:RNA