MicroRNA-138 Regulates Metastatic Potential of Bladder Cancer Through ZEB2.

BACKGROUND/AIMS: The cases of bladder cancer (BC) with poor prognosis largely result from the distal metastases of the primary tumor. Since microRNAs (miRNAs) play critical roles during cancer metastases, determination of the involved miRNAs in the regulation of the metastases of BC may provide novel therapeutic targets for BC treatment. Here, we aimed to study the role of miR-138 in regulation of BC cell invasion and metastases.

METHODS

We analyzed the levels of miR-138 and ZEB2, a key factor that regulates cancer cell invasion, in the BC specimens from the patients. We also studied the correlation between miR-138 and ZEB2. We performed bioinformatics analyses on the binding of miR-138 to the 3'-UTR of ZEB2 mRNA, and verified the biological effects of this binding through promoter luciferase reporter assay. The effects of miR-138-modification on BC cell invasion were evaluated in a transwell cell invasion assay and a scratch would healing assay.

RESULTS

We found that the levels of miR-138 were significantly decreased and the levels of ZEB2 were significantly increased in BC specimens, compared to the paired normal bladder tissue. Metastatic BC appeared to contained lower levels of miR-138. Moreover, miR-138 and ZEB2 inversely correlated in BC specimens. Bioinformatics analyses showed that miR-138 targeted the 3'-UTR of ZEB2 mRNA to inhibit its translation. Furthermore, miR-138 overexpression inhibited ZEB2-mediated cell invasion and metastases, while miR-138 depletion increased ZEB2-mediated cell invasion and metastases in BC cells.

CONCLUSION

Suppression of miR-138 in BC cells may promote ZEB2-mediated cancer invasion and metastases. Thus, miR-138 appears to be an intriguing therapeutic target to prevent metastases of BC.