Micro-RNA expression linked to cisplatin response in bladder cancer
MedWire News: Increasing expression of micro-RNA (miR)-34a increases sensitivity to chemotherapy in patients with muscle-invasive transitional cell carcinoma of the bladder (MI-TCC), study findings have revealed.
Just 50% of patients with MI-TCC respond to cisplatin-based chemotherapy, although efficacy in those who do respond is good. Thus, there is great value in identifying factors that predict response to chemotherapy, and either selectively treating patients most likely to respond, or increasing the response in all patients by manipulating those factors.
Various studies have suggested that alterations to the p53-Rb signaling axis predict progression of MI-TCC after cystectomy and it is also known that elements of this axis determine response to chemotherapy. However, difficulties in assaying p53 have left its exact role as an indicator of MI-TCC outcome unclear.
In contrast, MiR-34a, which is a downstream effector of p53, has been shown to predict disease progression in several cancers.
Noting this, Ralph deVere White (University of California, Davis, Sacramento, USA) and fellow researchers studied urothelial cells transfected with miR-34a to determine whether this could counter the effects of alterations to the p53-Rb signaling axis.
As reported in the International Journal of Cancer, increasing miR-34a expression through transfection and then treating with cisplatin dramatically reduced the ability of urothelial cells to proliferate and encouraged cell senescence relative to cells treated with cisplatin that had normal miR-34a expression.
Interestingly, levels of miR-34a were non-significantly lower in bladder tissue samples taken from patients with MI-TCC who did not respond to neoadjuvant treatment, compared with samples from patients who did respond to treatment. Further research suggested that the reduced expression of miR-34a was related to promoter methylation, but that other, unknown mechanisms also contributed to the reduction.
"The critical finding here is that increased miR-34a expression chemosensitizes transitional cell carcinoma cells to treatment with cisplatin regardless of which part of the p53-Rb signaling axis is dysfunctional," summarize the investigators.
"Our data suggest this is due to the ability of miR-34a to simultaneously target multiple components of this signaling axis," they conclude.
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By Philip Ford