TY - JOUR
T1 - Hepatocyte growth factor/scatter factor overexpression induces growth, abnormal development, and tumor formation in transgenic mouse livers
AU - Sakata, Hiromi
AU - Takayama, Hisashi
AU - Sharp, Richard
AU - Rubin, Jeffrey S.
AU - Merlino, Glenn
AU - LaRochelle, William J.
PY - 1996
Y1 - 1996
N2 - To investigate the in vivo role of hepatocyte growth factor/scatter factor (HGF/SF) in liver function, we generated transgenic mice using a mouse HGF/SF cDNA under the control of the mouse metallothionein gene promoter and 5'/3' flanking sequences. In adult HGF/SF transgenic mice, liver weight as a percentage of total body weight was at least twice that of wild-type mice. Comparison of transgenic and control liver morphology revealed dramatic heterogeneity in the size and appearance of hepatocytes as a distinctive feature of HGF/SF overexpression. Transgenic livers exhibited a significant increase in the number of small hepatocytes with a 2N DNA content, accounting for the observed increase in liver mass. The DNA labeling index of hepatocytes increased 11-fold at 4 weeks of age, when liver enlargement first became apparent, and was still elevated about 5-fold in adult HGF/SF transgenic mice. Moreover, hepatocytes isolated by perfusion of transgenic livers doubled every 2 days in culture, whereas little or no growth was observed with isolated control hepatocytes. The mechanistic basis of hepatocyte proliferation was elucidated as the chronic activation of the c- met proto-oncogene product. Met and substrates such as phosphatidylinositol 3-kinase, Src homology and collagen-like, pp60(c-src), focal adhesion kinase p125(FAK), and paxillin were associated with tyrosine-phosphorylated complexes in a hepatocyte cell line established from the transgenic liver. This proliferative stimulus triggered the formation of hepatocellular adenomas and/or carcinomas in most transgenic mice ≤1.5 years of age. Finally, the rate of transgenic mouse liver regeneration was increased 3- fold over control livers following partial hepatectomy. These data indicate that HGF/SF stimulates hepatic proliferation, regeneration, and oncogenesis when overexpressed in vivo, and suggest strongly that HGF/SF plays a prominent role in regulating normal liver growth, repair, and development.
AB - To investigate the in vivo role of hepatocyte growth factor/scatter factor (HGF/SF) in liver function, we generated transgenic mice using a mouse HGF/SF cDNA under the control of the mouse metallothionein gene promoter and 5'/3' flanking sequences. In adult HGF/SF transgenic mice, liver weight as a percentage of total body weight was at least twice that of wild-type mice. Comparison of transgenic and control liver morphology revealed dramatic heterogeneity in the size and appearance of hepatocytes as a distinctive feature of HGF/SF overexpression. Transgenic livers exhibited a significant increase in the number of small hepatocytes with a 2N DNA content, accounting for the observed increase in liver mass. The DNA labeling index of hepatocytes increased 11-fold at 4 weeks of age, when liver enlargement first became apparent, and was still elevated about 5-fold in adult HGF/SF transgenic mice. Moreover, hepatocytes isolated by perfusion of transgenic livers doubled every 2 days in culture, whereas little or no growth was observed with isolated control hepatocytes. The mechanistic basis of hepatocyte proliferation was elucidated as the chronic activation of the c- met proto-oncogene product. Met and substrates such as phosphatidylinositol 3-kinase, Src homology and collagen-like, pp60(c-src), focal adhesion kinase p125(FAK), and paxillin were associated with tyrosine-phosphorylated complexes in a hepatocyte cell line established from the transgenic liver. This proliferative stimulus triggered the formation of hepatocellular adenomas and/or carcinomas in most transgenic mice ≤1.5 years of age. Finally, the rate of transgenic mouse liver regeneration was increased 3- fold over control livers following partial hepatectomy. These data indicate that HGF/SF stimulates hepatic proliferation, regeneration, and oncogenesis when overexpressed in vivo, and suggest strongly that HGF/SF plays a prominent role in regulating normal liver growth, repair, and development.
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M3 - Article
C2 - 8930401
AN - SCOPUS:0029910845
SN - 1044-9523
VL - 7
SP - 1513
EP - 1523
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
IS - 11
ER -