Zhou Xu Dong, Sens Mary Ann, Garrett Scott H, Somji Seema, Park Seongmi, Gurel Volkan, Sens Donald A
Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58202, USA.
Toxicol Sci. 2006 Oct;93(2):322-30. doi: 10.1093/toxsci/kfl065. Epub 2006 Jul 19.
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).
本实验室提出，金属硫蛋白基因家族的第三种异构体（MT-3）可能是人类膀胱癌发生发展的生物标志物。对存档诊断标本进行MT-3免疫组化染色显示，63例良性膀胱标本中只有2例（3.17%）对MT-3蛋白有微弱反应。相比之下，107例高级别尿路上皮癌中的103例（96.26%）以及17例原位癌标本中的17例（100%）对MT-3蛋白染色呈阳性。对于低级别膀胱癌，结果显示48例标本中有30例（62.5%）表达MT-3蛋白。利用细胞培养模型（UROtsa）表明，Cd(+2)或As(+3)诱导尿路上皮细胞发生恶性转化并不需要MT-3蛋白的表达。相反，研究表明，在细胞培养中不表达MT-3基因的Cd(+2)和As(+3)转化细胞，当作为异种移植在裸鼠体内生长时会获得MT-3的表达。MCF-7、T-47D、Hs 578t、MDA-MB-231乳腺癌细胞系以及PC-3前列腺癌细胞系在作为异种移植生长时，也显示出MT-3表达增加。对MT-3 mRNA和蛋白表达的分析表明，转录后机制是MT-3蛋白积累的原因。这些结果提供了强有力的证据，表明MT-3可能是高级别膀胱癌发生发展的生物标志物，并且MT-3基因的表达不参与Cd(+2)和As(+3)诱导UROtsa细胞的体外恶性转化。
