MiR99a modulates MMP7 and MMP13 to regulate invasiveness of Kaposi's sarcoma.

Matrix metalloproteinases (MMPs) and microRNAs (miRNAs) are associated with Kaposi's sarcoma (KS) tumorigenesis. To date, the molecular basis underlying crosstalk of MMPs and miRNAs in KS remains unexplored. From the resected KS samples, we detected significant correlation of miRNA99a (miR99a), with MMP7 and MMP13, but not with MMP9. To define whether a causal link exists, we used a human KS line, SLK, to study the molecular basis of miR99a and activation of MMP7, MMP9, and MMP13. We found that overexpression of miR99a in SLK cells decreased MMP7 and MMP13, but not MMP9. Similarly, MiR99a inhibition in SLK cells activated MMP7 and MMP13, but did not affect expression of MMP9. These data suggest that MMP7 and MMP13 seem to be regulated by miR99a, while MMP9 seems to be regulated in a miR99a-independent manner. Inhibition of PI3k/Akt signaling pathway significantly abolished the effect of miR99a-knockdown on MMP7, but not MMP13 activation, while inhibition of ERK/MAPK signaling pathway significantly abolished the effect of miR99a-knockdown on MMP13, but not MMP7 activation. Taken together, our data suggest that miR99a inhibits MMP7 and MMP13 through PI3k/Akt and ERK/MAPK signaling pathway, respectively, in KS. Thus, miR99a, MMP7, and MMP13 appear to be promising therapeutic targets for preventing the metastasis of KS.