NF?B-mediated cyclin D1 expression by microRNA-21 influences renal cancer cell proliferation.

ABSTRACT: MicroRNAs regulate post-transcriptomic landscape in many tumors including renal cell carcinoma. We have recently shown significantly increased expression of miR-21 in renal tumors and that this miRNA contributes to the proliferation of renal cancer cells in culture. However, the mechanism by which miR-21 regulates renal cancer cell proliferation is poorly understood. Addiction to constitutive NF?B activity is hallmark of many cancers including renal cancer. Using miR-21 Sponge in renal cancer cells to block endogenous function of miR-21, we show inhibition of phosphorylation of p65 subunit of NF?B, IKK? and I?B, which results in attenuation of NF?B transcriptional activity. Subtle reduction in the tumor suppressor PTEN has been linked to various malignancies. We showed previously that miR-21 targeted PTEN in renal cancer cells. Inhibition of PTEN by siRNAs restored miR-21 Sponge-induced suppression of phosphorylation of p65, IKK?, I?B and NF?B transcriptional activity along with reversal of miR-21 Sponge-reduced phosphorylation of Akt. Expression of constitutively active Akt protected against miR-21 Sponge- and PTEN-mediated decrease in p65/IKK?/I?B phosphorylation and NF?B transcriptional activity. Furthermore, IKK? and p65 were required for miR-21-induced renal cancer cell proliferation. Interestingly, miR-21 controlled the expression of cyclin D1 through NF?B-dependent transcription. Finally, we demonstrate that miR-21-regulated renal cancer cell proliferation is mediated by cyclin D1 and CDK4. Together, our results establish a molecular order of a phosphatase-kinase couple involving PTEN/Akt/IKK? and NF?B-dependent cyclin D1 expression for renal carcinoma cell proliferation by increased miR-21 levels.

SUBMITTER: Bera A 

PROVIDER: S-EPMC3896302 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature