Yi-Ting Chen1,2,3,4, Wei-Ting Ou Yang2, Horng-Heng Juang5,6, Chien-Lun Chen5,7, Hsiao-Wei Chen2, Ke-Hung Tsui5, Ying-Hsu Chang8,9, Cheng-Han Tsai3, Chuen Hsueh2,10, Wei-Chao Liao2,11,12. 1. Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. 2. Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan. 3. Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. 4. Department of Nephrology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan. 5. Department of Urology, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 6. Department of Anatomy, College of Medicine, Chang Gung University, TaoYuan, Taiwan. 7. College of Medicine, Chang Gung University, Taoyuan, Taiwan. 8. Division of Urology, Department of Surgery, LinKou Chang Gung Memorial Hospital, Taoyuan, Taiwan. 9. Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. 10. Department of Pathology, Chang Gung Memorial Hospital, Linkou, Chang Gung University, College of Medicine, Taoyuan, Taiwan. 11. Department of Otolaryngology - Head & Neck Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 12. Center for General Education, Chang Gung University, Taoyuan, Taiwan.
Abstract
RATIONALE: Accumulating evidence has linked prolonged exposure to heavy metals to cancer occurrence in the urinary system. However, the specific biological mechanisms responsible for the association of heavy metals with the unusually high incidence of upper tract urothelial carcinoma in Taiwan are complex and incompletely understood. METHODS: To elucidate the specific biological mechanism and identify molecular indicators of the unusually high association of upper tract urothelial carcinoma with heavy metal exposure, protein expression following the treatment of T24 human bladder carcinoma and RT4 human bladder papilloma cell line models with arsenic (As) and cadmium (Cd) was studied. Proteomic changes in these cell models were integrated with data from a human bladder cancer (BLCA) tissue proteome to identify possible protein indicators of heavy metal exposure. RESULTS: After mass spectrometry based proteomic analysis and verification by Western blotting procedures, we identified 66 proteins that were up-regulated and 92 proteins that were down-regulated in RT4 cell extracts after treatment with As or Cd. Some 52 proteins were up-regulated and 136 proteins were down-regulated in T24 cell extracts after treatment with Cd. We further confirmed that down-expression of the PML (promyelocytic leukemia) protein was sustained for at least 75 days after exposure of bladder cells to As. Dysregulation of these cellular proteins by As was associated with three biological pathways. Immunohistochemical analyses of paraffin-embedded BLCA tissue slides confirmed that PML protein expression was decreased in BLCA tumor cells compared with adjacent noncancerous epithelial cells. CONCLUSIONS: These data suggest that PML may play an important role in the pathogenesis of BLCA and may be an indicator of heavy metal exposure in bladder cells.
RATIONALE: Accumulating evidence has linked prolonged exposure to heavy metals to cancer occurrence in the urinary system. However, the specific biological mechanisms responsible for the association of heavy metals with the unusually high incidence of upper tract urothelial carcinoma in Taiwan are complex and incompletely understood. METHODS: To elucidate the specific biological mechanism and identify molecular indicators of the unusually high association of upper tract urothelial carcinoma with heavy metal exposure, protein expression following the treatment of T24humanbladder carcinoma and RT4humanbladder papilloma cell line models with arsenic (As) and cadmium (Cd) was studied. Proteomic changes in these cell models were integrated with data from a humanbladder cancer (BLCA) tissue proteome to identify possible protein indicators of heavy metal exposure. RESULTS: After mass spectrometry based proteomic analysis and verification by Western blotting procedures, we identified 66 proteins that were up-regulated and 92 proteins that were down-regulated in RT4 cell extracts after treatment with As or Cd. Some 52 proteins were up-regulated and 136 proteins were down-regulated in T24 cell extracts after treatment with Cd. We further confirmed that down-expression of the PML (promyelocytic leukemia) protein was sustained for at least 75 days after exposure of bladder cells to As. Dysregulation of these cellular proteins by As was associated with three biological pathways. Immunohistochemical analyses of paraffin-embedded BLCA tissue slides confirmed that PML protein expression was decreased in BLCA tumor cells compared with adjacent noncancerous epithelial cells. CONCLUSIONS: These data suggest that PML may play an important role in the pathogenesis of BLCA and may be an indicator of heavy metal exposure in bladder cells.
Authors: Ana P Ferragut Cardoso; Mayukh Banerjee; Laila Al-Eryani; Mohammed Sayed; Daniel W Wilkey; Michael L Merchant; Juw W Park; J Christopher States Journal: Environ Health Perspect Date: 2022-01-24 Impact factor: 9.031