p53 deficiency accelerates induction and progression of esophageal and forestomach tumors in zinc-deficient mice.
The p53 tumor suppressor protein plays a pivotal role in preventing uncontrolled cellular proliferation. By contrast, zinc deprivation enhances esophageal cell proliferation and the induction of esophageal tumors in rodents by N-nitrosomethylbenzylamine (NMBA). We investigated whether p53 deficiency rendered zinc-deficient (ZD) mice more susceptible to NMBA-induced esophageal/forestomach carcinogenesis. At 6-7 weeks of age, p53 null (-/-), heterozygous (+/-), and wild-type (+/+) mice were placed on ZD or zinc-sufficient (ZS) diets to form six experimental groups: ZD:p53-/-; ZD:p53+/-; ZD:p53+/+; ZS:p53-/-; ZS:p53+/-; and ZS:p53+/+. After 3 weeks, 15-23 mice in each group were treated once with NMBA (2 mg/kg body weight). Control animals were untreated. Zinc deficiency alone induced unrestrained cellular proliferation in the esophagus and forestomach of p53-/- mice. Forestomach tumors were first detected in a ZD:p53-/- mouse at 13 days. By 30 days, 100% (21 of 21) of ZD:p53-/- mice developed forestomach tumors and 38% showed esophageal tumors versus 42 and 0% in ZS:p53-/- mice (P < 0.004, esophagus; P < 0.001, forestomach). ZD:p53-/- mice showed an accelerated progression to malignancy, with 10% of esophageal tumors and 38% of forestomach tumors presenting as carcinomas. Nearly 20% of ZD:p53-/- mice developed esophageal Barrett's metaplasia, a lesion not previously seen in NMBA-induced neoplasia. ZD:p53+/- mice had significantly higher tumor incidence than ZS:p53+/- mice. The order of tumor incidence in forestomach was as follows: naught incidence in ZS:p53+/+ mice; ZD:p53-/- > ZD:p53+/- > ZS:p53-/- > ZD:p53+/+ >/= ZS:p53+/- > ZS:p53+/+. The rapid rate of tumor induction/progression in ZD:p53-/- mice was accompanied by an increase in the rate of cell proliferation and a decrease in apoptosis. cDNA array expression analysis of known genes identified a 5-fold up-regulation of cytokeratin 14 mRNA expression in ZD:p53-/- versus ZS:p53-/- forestomach, a result showing gene-modulating effects of zinc deficiency. Cytokeratin 14 is a biomarker in human esophageal carcinogenesis. Our findings provide in vivo evidence for the collaboration of a deficiency of both p53 and zinc in esophageal carcinogenesis and reveal molecular targets of this collaboration.
Fong
Louise Y Y
LY
Kimmel Cancer Center, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. L_Fong@lac.jci.tju.edu
Ishii
Hideshi
H
Nguyen
Vu T
VT
Vecchione
Andrea
A
Farber
John L
JL
Croce
Carlo M
CM
Huebner
Kay
K
D000818:Animals; D002273:Carcinogens; D002455:Cell Division; D003433:Crosses, Genetic; D004032:Diet; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives*; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D005838:Genotype; D007633:Keratins / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D015032:Zinc / Q000172:deficiency*
D002273:Carcinogens; D016159:Tumor Suppressor Protein p53; D007633:Keratins; C014707:nitrosobenzylmethylamine; D015032:Zinc; D004128:Dimethylnitrosamine