Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver.
Pim-3, a proto-oncogene with serine/threonine kinase activity, was enhanced in hepatocellular carcinoma (HCC) tissues. To address the roles of Pim-3 in HCC development, we prepared transgenic mice that express human Pim-3 selectively in liver. The mice were born at a Mendelian ratio, were fertile and did not exhibit any apparent pathological changes in the liver until 1 year after birth. Pim-3-transgenic mouse-derived hepatocytes exhibited accelerated cell cycle progression. The administration of a potent hepatocarcinogen, diethylnitrosamine (DEN), induced accelerated proliferation of liver cells in Pim-3 transgenic mice in the early phase, compared with that observed for wild-type mice. Treatment with DEN induced lipid droplet accumulation with increased proliferating cell numbers 6 months after the treatment. Eventually, wild-type mice developed HCC with a frequency of 40% until 10 month after the treatment. Lipid accumulation was accelerated in Pim-3 transgenic mice with higher proliferating cell numbers, compared with that observed for wild-type mice. Pim-3 transgenic mice developed HCC with a higher incidence (80%) and a heavier burden, together with enhanced intratumoral CD31-positive vascular areas, compared with that observed for wild-type mice. These observations indicate that Pim-3 alone cannot cause, but can accelerate HCC development when induced by a hepatocarcinogen, such as DEN.
Wu
Y
Y
Department of Hematology and Hematology research Laboratory, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, PR China.
Wang
Y Y
YY
Nakamoto
Y
Y
Li
Y-Y
YY
Baba
T
T
Kaneko
S
S
Fujii
C
C
Mukaida
N
N
D000418:Albumins / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019076:Transgenes / Q000235:genetics*
D000418:Albumins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; C499249:PIM3 protein, human; D017346:Protein Serine-Threonine Kinases