Abstract
Urothelial bladder cancer (UBC) is a common genitourinary malignancy. MiR-31, a well-identified miRNA, exhibits diverse properties in different cancers. However, the specific functions and mechanisms of miR-31 in UBC have not been investigated. In this study, tumor samples, especially invasive UBC, showed significantly reduced level of miR-31, as compared with normal urothelium. Prognostic analysis using the EORTC model showed that down-regulation of miR-31 correlated with higher risks of recurrence and progression in noninvasive UBC cases. Remarkably, overexpression of miR-31 mimics in UBC cell lines inhibited cell proliferation, migration and invasion. Integrin α5 (ITGA5), an integrin family member, was subsequently identified as a direct target of miR-31 in UBC cells. When treated with mitomycin-C (MMC), miR-31-expressing UBC cells displayed lower survival and higher apoptotic rates, and deactivated Akt and ERK. These effects arising from miR-31 overexpression were abrogated by ITGA5 restoration. Furthermore, miR-31 markedly inhibited tumor growth and increased the effectiveness of MMC in UBC xenografts. In summary, our data suggest that miR-31 is a prognostic predictor and can serve as a potential therapeutic target of UBC.
Highlights
Bladder cancer is the fourth most frequent male malignancy in the United States and the most common genitourinary tract cancer in China
The current study focused on cases with noninvasive urothelial bladder carcinomas (UBC), which accounted for the majority (85/112) of our cohort
We demonstrated that the engagement of integrin induced resistance to MMC in UBC cells adhering to fibronectin [18]
Summary
More than 90% of bladder cancers are classified as urothelial bladder carcinomas (UBC), most of which present as the noninvasive form (stage Ta–T1). Noninvasive UBC is routinely treated with transurethral resection of bladder tumor (TURBT) and intravesical chemotherapy. More than 50% of tumors will recur and 10-20% progress to invasive disease (stage T2–T4) [2]. Patients with invasive UBC are suggested to receive radical cystectomy and systematic chemotherapy. They still have a poor 5-year survival rate of less than 60% [3]. One major dilemma in UBC treatment is inferior sensitivity or resistance to chemotherapy, but few advances have been made in clinical practice. Strategies based on new molecular targets are urgently needed in UBC diagnosis and therapeutics
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