Overexpression of Grb2 in inflammatory lesions and preneoplastic foci and tumors induced by N-nitrosodimethylamine in helicobacter hepaticus-infectedand -noninfected A/J mice
Ba. Diwan et al., Overexpression of Grb2 in inflammatory lesions and preneoplastic foci and tumors induced by N-nitrosodimethylamine in helicobacter hepaticus-infectedand -noninfected A/J mice, TOX PATHOL, 28(4), 2000, pp. 548-554
Growth factors bind to membrane receptor tyrosine kinases, resulting in aut
ophosphorylation and subsequent binding to proteins with SH2 domains, inclu
ding growth factor receptor-bound protein 2 (Grb2). Grb2 bridges receptors
to tyrosine kinase substrates such as SHC and SOS, which in turn facilitate
the activation of downstream signaling pathways, including Pas and mitogen
-activated protein kinase (MAPK). Overexpression of Grb2 has been demonstra
ted in several types of neoplasia but has not been investigated in liver tu
morigenesis. Here we investigated Grb2 expression in liver lesions in N-nit
rosodimethylamine (NDMA)-treated Helicobacter hepaticus-infected and -nonin
fected A/J mice at 1 year of age. Previously, we reported (6) that infectio
n promotes the development of these NDMA-initiated tumors. In controls, Grb
2 immunostaining was absent from normal hepatic tissues, whereas the inflam
matory lesions in infected livers were positive for cytoplasmic Grb2 in bot
h hepatocytes and infiltrating leukocytes. All preneoplastic foci (7 of 7),
15 of 27 adenomas, and 3 of 7 carcinomas were positive for Grb2 by immunos
taining in both infected and noninfected NDMA-initiated livers. Involvement
of Grb2 was confirmed by immunoblotting of similarly infected mice at 9 to
18 months of age, showing a 2.5- to 3.3-fold increase in Grb2 protein in i
nfected livers (p < 0.05 compared with uninfected controls) as well as in p
reneoplastic foci, adenomas, and carcinomas. These livers also showed a 2.5
- to 2.8-fold increase in total Ras protein. The results suggest that upreg
ulation of Grb2 is an early event in liver carcinogenesis, whether caused b
y the bacterial infection or by NDMA. Concomitant upregulation of Ras p21 w
ould ensure transmission of amplified signal from growth factors via Grb2.