Reference SummaryFong LY, Cancer Res 2003 Jan 1;63(1):186-95

Title

 p53 Deficiency Accelerates Induction and Progression of Esophageal and Forestomach Tumors in Zinc-deficient Mice.

Authors

 Fong LY; Ishii H; Nguyen VT; Vecchione A; Farber JL; Croce CM; Huebner K

Journal

 Cancer Res

Volume

 63

Issue

 1

Year

 2003

Pages

 186-95

Abstract

 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.

Links

 J:81055 – MGI References
12517797 – National Library of Medicine/PubMed

Strain Notes

Strain Note
B6.129S2-Trp53tm1Tyj/J Mice fed Zn deficient diet did not show any overt signs of deficiency such as retarded growth, hair loss and foci of alopecia, although testis Zn content was reduced 18-20% from normal levels.
Purchased 6-7 week old mice from The Jackson Laboratory.
B6.129S2-Trp53tm1Tyj/J Mice fed Zn deficient diet did not show any overt signs of deficiency such as retarded growth, hair loss and foci of alopecia, although testis Zn content was reduced 18-20% from normal levels.
Purchased 6-7 week old mice from The Jackson Laboratory.
C57BL/6J Mice fed Zn deficient diet did not show any overt signs of deficiency such as retarded growth, hair loss and foci of alopecia, although testis Zn content was reduced 18-20% from normal levels.
Purchased 6-7 week old mice from The Jackson Laboratory.

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
B6.129S2-Trp53tm1Tyj/J Esophagus - Glandular metaplasia
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Esophagus - Glandular

19
B6.129S2-Trp53tm1Tyj/J Esophagus - Glandular metaplasia
  • N-nitrosomethylbenzylamine (NMBA)
 Esophagus - Glandular

0
B6.129S2-Trp53tm1Tyj/J Esophagus hyperplasia
  • zinc-deficient
 Esophagus

very high
C57BL/6J Esophagus hyperplasia Esophagus

0
C57BL/6J Esophagus hyperplasia
  • zinc-deficient
 Esophagus

observed
B6.129S2-Trp53tm1Tyj/J Esophagus hyperplasia
  • zinc-deficient
 Esophagus

moderate
B6.129S2-Trp53tm1Tyj/J Esophagus hyperplasia Esophagus

very low
B6.129S2-Trp53tm1Tyj/J Esophagus hyperplasia
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Esophagus

observed
B6.129S2-Trp53tm1Tyj/J Esophagus hyperplasia Esophagus

moderate
B6.129S2-Trp53tm1Tyj/J Esophagus squamous cell carcinoma
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Esophagus

9.5
B6.129S2-Trp53tm1Tyj/J Esophagus tumor
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Esophagus

38
B6.129S2-Trp53tm1Tyj/J Esophagus tumor
  • N-nitrosomethylbenzylamine (NMBA)
 Esophagus

0
B6.129S2-Trp53tm1Tyj/J Esophagus tumor
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Esophagus

0
B6.129S2-Trp53tm1Tyj/J Esophagus tumor
  • N-nitrosomethylbenzylamine (NMBA)
 Esophagus

0
C57BL/6J Esophagus tumor
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Esophagus

0
C57BL/6J Esophagus tumor
  • N-nitrosomethylbenzylamine (NMBA)
 Esophagus

0
B6.129S2-Trp53tm1Tyj/J Forestomach - Squamocolumnar junction with the glandular stomach hyperplasia
  • zinc-deficient
 Forestomach - Squamocolumnar junction with the glandular stomach

very high
B6.129S2-Trp53tm1Tyj/J Forestomach - Squamocolumnar junction with the glandular stomach hyperplasia Forestomach - Squamocolumnar junction with the glandular stomach

moderate
B6.129S2-Trp53tm1Tyj/J Forestomach - Squamocolumnar junction with the glandular stomach papilloma
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Forestomach - Squamocolumnar junction with the glandular stomach

observed
B6.129S2-Trp53tm1Tyj/J Forestomach - Squamocolumnar junction with the glandular stomach tumor
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Forestomach - Squamocolumnar junction with the glandular stomach

100
B6.129S2-Trp53tm1Tyj/J Forestomach - Squamocolumnar junction with the glandular stomach tumor
  • N-nitrosomethylbenzylamine (NMBA)
 Forestomach - Squamocolumnar junction with the glandular stomach

74
B6.129S2-Trp53tm1Tyj/J Forestomach - Squamocolumnar junction with the glandular stomach tumor
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Forestomach - Squamocolumnar junction with the glandular stomach

88
B6.129S2-Trp53tm1Tyj/J Forestomach - Squamocolumnar junction with the glandular stomach tumor
  • N-nitrosomethylbenzylamine (NMBA)
 Forestomach - Squamocolumnar junction with the glandular stomach

19
C57BL/6J Forestomach - Squamocolumnar junction with the glandular stomach tumor
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Forestomach - Squamocolumnar junction with the glandular stomach

13
C57BL/6J Forestomach - Squamocolumnar junction with the glandular stomach tumor
  • N-nitrosomethylbenzylamine (NMBA)
 Forestomach - Squamocolumnar junction with the glandular stomach

0
B6.129S2-Trp53tm1Tyj/J Forestomach hyperplasia
  • zinc-deficient
 Forestomach

very high
C57BL/6J Forestomach hyperplasia
  • zinc-deficient
 Forestomach

observed
C57BL/6J Forestomach hyperplasia Forestomach

0
B6.129S2-Trp53tm1Tyj/J Forestomach hyperplasia
  • zinc-deficient
 Forestomach

moderate
B6.129S2-Trp53tm1Tyj/J Forestomach hyperplasia Forestomach

very low
B6.129S2-Trp53tm1Tyj/J Forestomach hyperplasia Forestomach

moderate
B6.129S2-Trp53tm1Tyj/J Forestomach papilloma
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Forestomach

observed
B6.129S2-Trp53tm1Tyj/J Forestomach squamous cell carcinoma
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Forestomach

38
B6.129S2-Trp53tm1Tyj/J Forestomach squamous cell carcinoma
  • N-nitrosomethylbenzylamine (NMBA)
 Forestomach

5.3
B6.129S2-Trp53tm1Tyj/J Forestomach squamous cell carcinoma
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Forestomach

13
B6.129S2-Trp53tm1Tyj/J Forestomach tumor
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Forestomach

100
B6.129S2-Trp53tm1Tyj/J Forestomach tumor
  • N-nitrosomethylbenzylamine (NMBA)
 Forestomach

42
B6.129S2-Trp53tm1Tyj/J Forestomach tumor
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Forestomach

69
B6.129S2-Trp53tm1Tyj/J Forestomach tumor
  • N-nitrosomethylbenzylamine (NMBA)
 Forestomach

6.3
C57BL/6J Forestomach tumor
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Forestomach

13
C57BL/6J Forestomach tumor
  • N-nitrosomethylbenzylamine (NMBA)
 Forestomach

0
B6.129S2-Trp53tm1Tyj/J Leukocyte lymphoma
  • zinc-deficient
 Leukocyte

40 - 70
B6.129S2-Trp53tm1Tyj/J Leukocyte lymphoma Thymus

40
B6.129S2-Trp53tm1Tyj/J Leukocyte lymphoma
  • zinc-deficient
 Thymus

10
B6.129S2-Trp53tm1Tyj/J Leukocyte lymphoma Thymus

0
C57BL/6J Leukocyte lymphoma Leukocyte

0
C57BL/6J Leukocyte lymphoma
  • zinc-deficient
 Leukocyte

0
B6.129S2-Trp53tm1Tyj/J Leukocyte lymphoma
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Thymus

4.3
B6.129S2-Trp53tm1Tyj/J Leukocyte lymphoma
  • N-nitrosomethylbenzylamine (NMBA)
  • zinc-deficient
 Leukocyte

35
B6.129S2-Trp53tm1Tyj/J Leukocyte lymphoma
  • N-nitrosomethylbenzylamine (NMBA)
 Leukocyte

16