Hepatic tumors induced by carbon tetrachloride in transgenic mice carrying a human c-H-ras proto-oncogene without mutations.
Hepatic tumors were generated in mice by repeated administration of carbon tetrachloride (CCl4). Eight transgenic (Tg) mice carrying a human c-H-ras proto-oncogene (rasH2 line) and 9 non-Tg mice were killed at 20 weeks. Tg mice developed more tumors than did non-Tg littermates. Most tumors were neoplastic nodules, but 1 hepatocellular carcinoma (HCC) was found in a Tg mouse at 20 weeks. Three Tg and 2 non-Tg mice were kept without further administration of CCl4. Two Tg mice died at 30 weeks of HCC with intra-abdominal bleeding, and 1 Tg mouse developed HCC with a mesenteric metastasis at 32 weeks. No HCC was found in 2 non-Tg mice at 32 weeks. Although mutations at codon 12, 13, and 61 of the H-ras gene are often found in murine hepatocarcinogenesis, neither the tumors, including one HCC, nor the normal cells revealed any such mutations. These results showed that the unmutated human c-H-ras gene facilitates malignant transformation of hepatocytes when continuous liver-cell death and regeneration is caused by repeated administration of CCl4.
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
S
S
Tsunematsu
H
H
Saito
T
T
Kagawa
T
T
Morizane
J
J
Hata
T
T
Nakamura
H
H
Ishii
M
M
Tsuchiya
T
T
Nomura
M
M
Katsuki
D000818:Animals; D001483:Base Sequence; D002251:Carbon Tetrachloride; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics* / Q000648:ultrastructure; D016923:Cell Death; D004273:DNA, Neoplasm / Q000032:analysis; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000648:ultrastructure; D008115:Liver Regeneration / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D017354:Point Mutation; D000090063:Proto-Oncogene Mas; D018709:Statistics, Nonparametric
D004273:DNA, Neoplasm; C000715470:MAS1 protein, human; D015345:Oligonucleotide Probes; D000090063:Proto-Oncogene Mas; D002251:Carbon Tetrachloride