Dysregulation of DNA repair pathways in a transforming growth factor alpha/c-myc transgenic mouse model of accelerated hepatocarcinogenesis.
Previous work from our laboratory has implicated oxidative DNA damage and genetic instability in the etiology of transforming growth factor-alpha (TGFalpha)/c-myc-associated hepatocarcinogenesis. In contrast, oxidative DNA damage was lower in c-myc single-transgenic mice, consistent with less chromosomal damage and with later and more benign tumor formation. We examined whether defects in the DNA repair pathways contribute to the acceleration of liver cancer in TGFalpha/c-myc mice. A cDNA expression array containing 140 known genes and multiplex RT-PCR were used to compare the basal levels of expression of DNA repair genes at the dysplastic stage. Thirty-five percent (8/23) and 43% (10/23) of DNA repair genes were constitutively up-regulated in 10-week-old TGFalpha/c-myc and c-myc transgenic livers, respectively, compared with wild-type controls. The commonly up-regulated genes were OGG1 and NTH1 of base excision repair; ERCC5, RAD23A, and RAD23B of nucleotide excision repair; and RAD50, RAD52, and RAD54 involved in DNA strand break repair. Additional treatment with a peroxisome proliferator, Wy-14,643, known to increase the level of oxidants in the liver, failed to induce a further increase in the expression level of DNA repair enzymes in TGFalpha/c-myc but not in c-myc or wild-type livers. Moreover, expression of several genes, including Ku80, PMS2, and ATM, was decreased in TGFalpha/c-myc livers, suggesting a fault or inefficient activation of the DNA repair pathway upon induction of oxidative stress. Together, the results show that DNA damage response is attenuated in TGFalpha/c-myc mice, creating a condition that may contribute to acceleration of liver cancer in this model.
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Koji
K
Hironaka
Valentina M
VM
Factor
Diego F
DF
Calvisi
Elizabeth A
EA
Conner
Snorri S
SS
Thorgeirsson
D000818:Animals; D004249:DNA Damage; D004260:DNA Repair; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D016259:Genes, myc / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism; D008113:Liver Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011743:Pyrimidines / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000502:physiology*
D011743:Pyrimidines; D016211:Transforming Growth Factor alpha; C006253:pirinixic acid