Hepatocyte-specific activation of NF-kappaB does not aggravate chemical hepatocarcinogenesis in transgenic mice.
The NF-kappaB signalling pathway plays important roles in liver organogenesis and carcinogenesis. Mouse embryos deficient in IKKbeta die in mid-gestation, due to excessive apoptosis of hepatoblasts. Although activation of the NF-kappaB signalling pathway has been demonstrated in human hepatocellular carcinoma, the role of NF-kappaB is controversial. Here, we have generated transgenic mice in which a constitutively active form of IKKbeta was expressed in a hepatocyte-specific manner. Using electrophoretic mobility shift assay, we documented increased NF-kappaB activities and up-regulated levels of NF-kappaB downstream target genes, Bcl-xL and STAT5, in the transgenic mouse livers. These results confirmed that the NF-kappaB pathway was activated in the livers of the transgenic mice. However, there was no significant difference in tumour formation between transgenic and wild-type mice up to an age of 50 weeks. When we treated the transgenic mice with the chemical carcinogen diethylnitrosamine (DEN), we observed no significant differences in the incidence and size of liver tumours formed in these mice with and without DEN treatment at 35 weeks of age, suggesting that the activated NF-kappaB pathway in the livers of the transgenic mice did not enhance hepatocarcinogenesis. Interestingly, some of the transient transgenic embryos (E12.5) had abnormal excessive accumulation of nucleated red blood cells in their developing livers. In summary, NF-kappaB activation in hepatocytes did not significantly affect chemical hepatocarcinogenesis. In addition, the TTR/IKKCA transgenic mice may serve as a useful model for studying the role of NF-kappaB activation in hepatocarcinogenesis as well as inflammatory and metabolic diseases.
Yau
T-O
TO
Liver Cancer and Hepatitis Research Laboratory, Department of Pathology, The University of Hong Kong, Hong Kong.
Chan
C-F
CF
Gee-San Lam
S
S
Cheung
O-F
OF
Ching
Y-P
YP
Jin
D-Y
DY
Sham
M-H
MH
Ng
I O L
IO
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism*; D045744:Cell Line, Tumor; D004052:Diethylnitrosamine; D024202:Electrophoretic Mobility Shift Assay; D022781:Hepatocytes / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000196:embryology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism*; D014162:Transfection / Q000379:methods
D016328:NF-kappa B; D004052:Diethylnitrosamine; D051550:I-kappa B Kinase