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Abstract
Resistance to cisplatin-based chemotherapy is a major cause of treatment failure in advanced bladder cancer (BC) patients. There is increasing evidence that microRNAs are involved in the development and progression of BC. However, little is known about the function of microRNAs in predicting the effect of adjuvant chemotherapy on BC survival and regulating response to cisplatin. To address this issue, we employed RT-qPCR to evaluate the clinical significance of miR-203 expression in 108 tissues of BC patients receiving cisplatin-based adjuvant chemotherapy, and performed in vitro studies to explore chemotherapeutic sensitivity to cisplatin in miR-203 overexpressing BC cells. We found miR-203 levels were significantly lower in BC progression group than non-progression group (P<0.001). ROC curve analysis illustrated miR-203 could significantly distinguish progressed patients from those without progression (P<0.001), yielding an area under the ROC curve of 0.839 (95% CI, 0.756–0.903). Moreover, low miR-203 expression correlated with shortened progression free survival (PFS) and overall survival (OS) of BC patients, and was an independent prognostic factor. Overexpression of miR-203 in 5637 and T24 BC cells could decrease cell viability, enhance cisplatin cytotoxicity, and promote apoptosis. Western blotting and luciferase reporter assay showed Bcl-w and Survivin were direct downstream targets of miR-203. There was also a significant inverse association between miR-203 and Bcl-w or Survivin expression in BC tissues (r = -0.781, -0.740, both P<0.001). In conclusion, decreased miR-203 predicts progression and poor prognosis for BC patients treated with cisplatin-based chemotherapy while miR-203 overexpression can enhance cisplatin sensitization by promoting apoptosis via directly targeting Bcl-w and Survivin.
Highlights
Worldwide, bladder cancer (BC) is the second most common malignancy of the urinary system, with about 386,300 new cases and 150,200 deaths annually[1]
Receiver operating characteristic (ROC) curves analyses illustrated miR-203 yielded an area under the ROC curve (AUC) value of 0.839 in distinguishing patients with progression from those without progression, which was more accurate than guessing (P
Postoperative cisplatin-based chemotherapy has been widely used for muscle invasive or metastatic BC, resulting a response in up to 70% patients[21]
Summary
Bladder cancer (BC) is the second most common malignancy of the urinary system, with about 386,300 new cases and 150,200 deaths annually[1]. There is an urgent need to predict the effect of adjuvant chemotherapy on BC survival and understand the mechanisms that prevent response to chemotherapy
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