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.
© 2019 John Wiley & Sons, Ltd.