This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fong, L. Y. Y. Articles by Magee, P. N. Search for Related Content PubMed PubMed Citation Articles by Fong, L. Y. Y. Articles by Magee, P. N.

Early Deregulation of the p16^ink4a-Cyclin D1/Cyclin-dependent Kinase 4-Retinoblastoma Pathway in Cell Proliferation-driven Esophageal Tumorigenesis in Zinc-deficient Rats¹

Department of Microbiology and Immunology, Kimmel Cancer Institute [L. Y. Y. F., V. T. N., K. H., P. N. M.] and Department of Pathology, Anatomy & Cell Biology [J. L. F.], Thomas Jefferson University, Philadelphia, Pennsylvania 19107

The p16^ink4a-cyclin D1/cyclin-dependent kinase 4 (Cdk4)-retinoblastoma (Rb) pathway has emerged as a critical target in oncogenesis. The zinc-deficient (ZD), N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal cancer model provides a tool to study cell proliferation and cell cycle control in cancer initiation. Weanling rats were fed a ZD or zinc-sufficient (ZS) diet for 5 weeks, and then given a dose of NMBA. After 14 weeks, esophageal tumor incidence was 88% in ZD rats with highly proliferative esophagi versus 0% in ZS rats. Expression of p16^ink4a, cyclin D1, Cdk4, and Rb in relation to that of proliferating cell nuclear antigen was characterized in esophagi by immunohistochemistry at 0, 24, and 48 h, and 1, 3, 7, 10, and 14 weeks after NMBA treatment. As early as 24 h, proliferating cell nuclear antigen-positive focal hyperplastic lesions were detected in the suprabasal layers of ZD esophagi. At the same time, overexpression of cyclin D1, Cdk4, and Rb was found in the corresponding lesion in adjacent esophageal sections. By contrast, p16^ink4a expression was reduced or absent. At all time points, p16^ink4a showed reduced nuclear staining in ZD esophagi compared with that in ZS esophagi. In addition, increased expression of the hyperphosphorylated forms of Rb was detected in ZD esophagi by immunoblotting. Importantly, tumors were consistently observed in ZD esophagi at very early time points. These data, obtained using a unique in vivo model for esophageal cancer with rapid tumor induction, provide strong evidence for a link between deregulation of the p16^ink4a-cyclin D1/Cdk4-Rb pathway and the initiation of esophageal tumors.

This article has been cited by other articles:

				G. Jayachandran, J.-i. Sazaki, M. Nishizaki, K. Xu, L. Girard, J. D. Minna, J. A. Roth, and L. Ji Fragile Histidine Triad Mediated Tumor Suppression of Lung Cancer by Targeting Multiple Components of the Ras/Rho GTPase Molecular Switch Cancer Res., November 1, 2007; 67(21): 10379 - 10388. [Abstract] [Full Text] [PDF]

				L. Y.Y. Fong, Y. Jiang, and J. L. Farber Zinc deficiency potentiates induction and progression of lingual and esophageal tumors in p53-deficient mice Carcinogenesis, July 1, 2006; 27(7): 1489 - 1496. [Abstract] [Full Text] [PDF]

				C.-G. Liu, L. Zhang, Y. Jiang, D. Chatterjee, C. M. Croce, K. Huebner, and L. Y.Y. Fong Modulation of Gene Expression in Precancerous Rat Esophagus by Dietary Zinc Deficit and Replenishment Cancer Res., September 1, 2005; 65(17): 7790 - 7799. [Abstract] [Full Text] [PDF]

				L. Y. Y. Fong, L. Zhang, Y. Jiang, and J. L. Farber Dietary Zinc Modulation of COX-2 Expression and Lingual and Esophageal Carcinogenesis in Rats J Natl Cancer Inst, January 5, 2005; 97(1): 40 - 50. [Abstract] [Full Text] [PDF]

				L. Y. Y. Fong, R. Mancini, H. Nakagawa, A. K. Rustgi, and K. Huebner Combined Cyclin D1 Overexpression and Zinc Deficiency Disrupts Cell Cycle and Accelerates Mouse Forestomach Carcinogenesis Cancer Res., July 15, 2003; 63(14): 4244 - 4252. [Abstract] [Full Text] [PDF]

				L. Y. Y. Fong, H. Ishii, V. T. Nguyen, A. Vecchione, J. L. Farber, C. M. Croce, and K. Huebner p53 Deficiency Accelerates Induction and Progression of Esophageal and Forestomach Tumors in Zinc-deficient Mice Cancer Res., January 1, 2003; 63(1): 186 - 195. [Abstract] [Full Text] [PDF]

				J. Smeds, P. Berggren, X. Ma, Z. Xu, K. Hemminki, and R. Kumar Genetic status of cell cycle regulators in squamous cell carcinoma of the oesophagus: the CDKN2A (p16INK4a and p14ARF ) and p53 genes are major targets for inactivation Carcinogenesis, April 1, 2002; 23(4): 645 - 655. [Abstract] [Full Text] [PDF]

				L. Y. Y. Fong, V. T. Nguyen, and J. L. Farber Esophageal Cancer Prevention in Zinc-Deficient Rats: Rapid Induction of Apoptosis by Replenishing Zinc J Natl Cancer Inst, October 17, 2001; 93(20): 1525 - 1533. [Abstract] [Full Text] [PDF]

				F. Biramijamal, A. Allameh, P. Mirbod, H.-J. Groene, R. Koomagi, and M. Hollstein Unusual Profile and High Prevalence of p53 Mutations in Esophageal Squamous Cell Carcinomas from Northern Iran Cancer Res., April 1, 2001; 61(7): 3119 - 3123. [Abstract] [Full Text]

				L. Y. Y. Fong, V. T. Nguyen, A. E. Pegg, and P. N. Magee {{alpha}}-Difluoromethylornithine Induction of Apoptosis: A Mechanism Which Reverses Pre-established Cell Proliferation and Cancer Initiation in Esophageal Carcinogenesis in Zinc-deficient Rats Cancer Epidemiol. Biomarkers Prev., March 1, 2001; 10(3): 191 - 199. [Abstract] [Full Text]