Abstract
In treating bladder cancer, determining the molecular mechanisms of tumor invasion, metastasis, and drug resistance are urgent to improving long-term patient survival. One of the metabolic enzymes, aldo-keto reductase 1C1 (AKR1C1), plays an essential role in cancer invasion/metastasis and chemoresistance. In orthotopic xenograft models of a human bladder cancer cell line, UM-UC-3, metastatic sublines were established from tumors in the liver, lung, and bone. These cells possessed elevated levels of EMT-associated markers, such as Snail, Slug, or CD44, and exhibited enhanced invasion. By microarray analysis, AKR1C1 was found to be up-regulated in metastatic lesions, which was verified in metastatic human bladder cancer specimens. Decreased invasion caused by AKR1C1 knockdown suggests a novel role of AKR1C1 in cancer invasion, which is probably due to the regulation of Rac1, Src, or Akt. An inflammatory cytokine, interleukin-1β, was found to increase AKR1C1 in bladder cancer cell lines. One particular non-steroidal anti-inflammatory drug, flufenamic acid, antagonized AKR1C1 and decreased the cisplatin-resistance and invasion potential of metastatic sublines. These data uncover the crucial role of AKR1C1 in regulating both metastasis and drug resistance; as a result, AKR1C1 should be a potent molecular target in invasive bladder cancer treatment.
Highlights
The epithelial-mesenchymal transition (EMT) is known to be the initial step of invasion and metastasis in bladder cancer, and this process is related to cancer stemness[8,9]
The cells were inoculated into the bladders of two nude mice through a urethral catheter, and the labeled cancer cells were successfully detected by bioluminescent imaging (BLI) (Fig. 1a)
In our model, circulating cancer cells were observed in the bloodstream of the mice[34], and we could establish three metastatic sublines from the nodules found in the lungs, liver, and bone
Summary
The epithelial-mesenchymal transition (EMT) is known to be the initial step of invasion and metastasis in bladder cancer, and this process is related to cancer stemness[8,9]. Murine models are potentially useful systems for elucidating the molecular mechanisms underlying the invasion, metastasis, and drug resistance associated with bladder cancer aggressiveness. Using bladder cancer cells that are genetically labeled with luciferase, a single metastatic cell can be monitored in vivo and a metastatic subpopulation can be purified[30] Using this orthotopic xenograft murine model, we investigated the molecular mechanism of bladder cancer metastasis for identifying a therapeutic candidate reagent
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