Gender-dependent hepatic alterations in H-ras12V transgenic mice.
OBJECTIVE
Although it has been proposed that Ras and related signal pathways play important roles in hepatocarcinogenesis, appropriate in vivo models are lacking.


METHODS
Two hepatocellular carcinoma lines were established using pronuclear microinjection techniques to create an insertion of the H-ras12V transgene under the control of the albumin enhancer/promoter. The resulting phenotypes and related molecular events were then examined.


RESULTS
Male (but not female) transgenic mice older than 2 months showed hepatic alterations with a high degree of reproducibility, as compared to the wild-type mice. The liver/body-weight ratios were lower for the females than for the males. The transgene-carrying line 28 was investigated extensively with respect to molecular differences between the genders. Male hepatocytes showed higher Ras activity and higher reactive oxygen species (ROS) levels than female hepatocytes. The female hepatocytes showed higher expression levels of p53 and p21Waf1/Cip1, enhanced cytochrome c release, which correlated with cell cycle arrest, and higher levels of hypodiploid cell formation, as compared to the male hepatocytes.


CONCLUSIONS
The gender-related differences in molecular responses to activated Ras may have implications for the prevalence of hepatic alterations in males. Our transgenic mice represent a potentially valuable animal model for future investigations.
Wang
Ai-Guo
AG
Laboratory of Human Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, South Korea.
Moon
Hyung-Bae
HB
Lee
Mi-Ran
MR
Hwang
Chae Young
CY
Kwon
Ki-Sun
KS
Yu
Seong-Lan
SL
Kim
Yong-Sung
YS
Kim
Mirang
M
Kim
Jin-Man
JM
Kim
Sang-Keun
SK
Lee
Tae-Hoon
TH
Moon
Eun-Yi
EY
Lee
Dong-Seok
DS
Yu
Dae-Yeul
DY
D000418:Albumins / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D011905:Genes, ras; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D008113:Liver Neoplasms; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012737:Sex Factors; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D000418:Albumins; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins