Metastatic
renal cancer manifests multiple signatures of gene expression. Deviation in expression of mature
miRNAs has been linked to human
cancers. Importance of miR-21 in
renal cell carcinomas is proposed from profiling studies using
tumor tissue samples. However, the role of miR-21 function in causing
renal cancer cell proliferation and invasion has not yet been shown. Using cultured
renal carcinoma cells, we demonstrate enhanced expression of mature miR-21 along with pre-and pri-miR-21 by increased transcription compared to normal proximal tubular epithelial cells. Overexpression of miR-21 Sponge to quench endogenous miR-21 levels inhibited proliferation, migration and invasion of
renal cancer cells. In the absence of mutation in the PTEN tumor suppressor gene,
PTEN protein levels are frequently downregulated in
renal cancer. We show that miR-21 targets PTEN
mRNA 3'untranslated region to decrease
PTEN protein expression and augments Akt phosphorylation in
renal cancer cells. Downregulation of PTEN as well as overexpression of constitutively active Akt
kinase prevented miR-21 Sponge-induced inhibition of
renal cancer cell proliferation and migration. Moreover, we show that miR-21 Sponge inhibited the inactivating phosphorylation of the
tumor suppressor protein tuberin and attenuated
TORC1 activation. Finally, we demonstrate that expression of constitutively active
TORC1 attenuated miR-21 Sponge-mediated suppression of proliferation and migration of
renal cancer cells. Our results uncover a layer of post-transcriptional regulation of PTEN by transcriptional activation of miR-21 to force the canonical oncogenic Akt/
TORC1 signaling conduit to drive
renal cancer cell proliferation and invasion.