title: Enhanced expression of metallothionein isoform 3 protein in tumor heterotransplants derived from As+3- and Cd+2-transformed human urothelial cells.
abstract: This laboratory has proposed that the third isoform of the metallothionein gene family (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 posttranscriptional 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).
authors.affiliation: Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58202, USA.
authors.forename: Xu Dong
authors.initials: XD
authors.lastname: Zhou
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Sens
authors.forename: Scott H
authors.initials: SH
authors.lastname: Garrett
authors.forename: Seema
authors.initials: S
authors.lastname: Somji
authors.forename: Seongmi
authors.initials: S
authors.lastname: Park
authors.forename: Volkan
authors.initials: V
authors.lastname: Gurel
authors.forename: Donald A
authors.initials: DA
authors.lastname: Sens
mesh_terms: D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000378:metabolism; D002104:Cadmium / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008668:Metallothionein / Q000032:analysis / Q000235:genetics*; D000090023:Metallothionein 3; D051379:Mice; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000378:metabolism; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000032:analysis; D014183:Transplantation, Heterologous; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D000090023:Metallothionein 3; C000715430:Mt3 protein, mouse; D020033:Protein Isoforms; D012333:RNA, Messenger; D002104:Cadmium; D008668:Metallothionein; D001151:Arsenic