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ToxSci Advance Access published online on July 19, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl065
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received June 5, 2006
Accepted July 14, 2006

Environmental Toxicology

Enhanced Expression of Metallothionein Isoform 3 (MT-3) Protein in Tumor Heterotransplants Derived From As+3 and Cd+2 Transformed Human Urothelial Cells

Xu Dong Zhou 1, Mary Ann Sens 1, Scott H. Garrett 1, Seema Somji 1, Seongmi Park 1, Volkan Gurel 1, and Donald A. Sens 1 *

1 Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202

* To whom correspondence should be addressed.
Donald A. Sens, E-mail: dsens{at}medicine.nodak.edu


  Abstract

This laboratory has proposed that MT-3 might be a biomarker for the development of human bladder cancer. Immunohistochemical staining of MT-3 on archival diagnostic specimens showed that only 2 of 63 (3.17%) benign bladder specimens had even weak reactivity for the MT-3 protein. In contrast, 103 of 107 (96.26%) high grade urothelial cancers and 17 of 17 (100%) specimens of carcinoma in situ stained positive for the MT-3 protein. For low grade bladder cancer it was shown that 30 of 48 specimens (62.5%) expressed the MT-3 protein. Using a cell culture model (UROtsa), it was demonstrated that expression of the MT-3 protein was not required for malignant transformation of urothelial cells by either Cd+2 or As+3. In contrast, it was shown that the cells transformed by Cd+2 and As+3 that did not express the MT-3 gene in cell culture, gained expression of MT-3 when grown as heterotransplants in nude mice. The gain in MT-3 expression when cells were grown as heterotransplants was also shown to occur for the MCF-7, T-47D, Hs 578t, MDA-MB-231 breast cancer and the PC-3 prostate cancer cell lines. An analysis of MT-3 mRNA and protein expression suggested that a post-transcriptional mechanism was responsible for accumulation of the MT-3 protein. The results provide strong evidence that MT-3 could be a biomarker for the development of high grade bladder cancer and that the expression of the MT-3 gene is not involved in the in vitro malignant transformation of UROtsa cells by Cd+2 and As+3.

Keywords: metallothionein; biomarker; bladder cancer; cadmium; arsenic; transformation.
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S. Somji, X. D. Zhou, S. H. Garrett, M. A. Sens, and D. A. Sens
Urothelial Cells Malignantly Transformed by Exposure to Cadmium (Cd+2) and Arsenite (As+3) Have Increased Resistance to Cd+2 and As+3-Induced Cell Death
Toxicol. Sci., December 1, 2006; 94(2): 293 - 301.
[Abstract] [Full Text] [PDF]


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