A miR-135b-TAZ positive feedback loop promotes epithelial-mesenchymal transition (EMT) and tumorigenesis in osteosarcoma.

Transcriptional co-activator with PDZ-binding motif (TAZ) is a WW domain-containing protein that regulates mesenchymal differentiation and organ development. It is also a downstream effector of the Hippo signaling pathway, which has been implicated in epithelial-mesenchymal transition (EMT) and tumorigenesis. However, the molecular mechanisms underlying TAZ function in these processes in the context of osteosarcoma (OS) are not well understood. We addressed this in the present study using U2OS and HOS cell lines. We found that TAZ signaling is maintained via a previously undescribed micro (mi)RNA-dependent positive feedback loop. The miRNA miR-135b, which is directly induced by TAZ, suppressed the TAZ inhibitors large tumor suppressor 2, adenomatous polyposis coli, and glycogen synthase kinase 3β, thereby amplifying TAZ signaling and inducing EMT. Overexpression of miR-135b caused constitutive activation of TAZ, which rescued the inhibition of cell proliferation and EMT induced by TAZ knockdown. These results provide evidence that TAZ and miR-135b engage in a positive feedback loop to regulate EMT and metastasis in OS, and suggest that both factors can be therapeutic targets for OS treatment.