Rho GDI β promotes Sp1/ MMP ‐2 expression and bladder cancer invasion through perturbing miR‐200c‐targeted JNK 2 protein translation

Our most recent studies demonstrate that Rho GDI β is able to promote human bladder cancer ( BC ) invasion and metastasis in an X‐link inhibitor of apoptosis protein‐dependent fashion accompanied by increased levels of matrix metalloproteinase ( MMP )‐2 protein expression. We also found that Rho GDI β and MMP ‐2 protein expressions are consistently upregulated in both invasive BC tissues and cell lines. In the present study, we show that knockdown of Rho GDI β inhibited MMP ‐2 protein expression accompanied by a reduction of invasion in human BC cells, whereas ectopic expression of Rho GDI β upregulated MMP ‐2 protein expression and promoted invasion as well. The mechanistic studies indicated that MMP ‐2 was upregulated by Rho GDI β at the transcriptional level by increased specific binding of the transcription factor Sp1 to the mmp‐2 promoter region. Further investigation revealed that Rho GDI β overexpression led to downregulation of miR‐200c, whereas miR‐200c was able directly to target 3′‐ UTR of jnk2 mRNA and attenuated JNK 2 protein translation, which resulted in attenuation of Sp1 mRNA and protein expression in turn, inhibiting Sp1‐dependent mmp‐2 transcription. Collectively, our studies demonstrate that Rho GDI β overexpression inhibits miR‐200c abundance, which consequently results in increases of JNK 2 protein translation, Sp1 expression, mmp‐2 transcription, and BC invasion. These findings, together with our previous results showing X‐link inhibitor of apoptosis protein mediating mRNA stabilization of both Rho GDI β and mmp‐2 , reveal the nature of the MMP ‐2 regulatory network, which leads to MMP ‐2 overexpression and BC invasion.