MiR-21 Is Regulated By The β-catenin/STAT3 Pathway And Promotes Glioma Cell Invasion

Gliomas account for more than 50% of primary tumors in central nervous system, glioblastoma multiform (GBMs) is the most frequent and malignant histologic type. Current therapies for GBMs include surgery, radiotherapy, and chemotherapy, but patients afflicted with GBM survive on average less than 1 year due to the rapidness and invasiveness of tumor growth. Although the molecular mechanisms that contribute to malignant progression and invasive growth of gliomas have become increasingly clear in the past decades, much still remains to be learned.(β-catenin acts as an important player in both cell adhesion and signal transduction, its cytoplasmic stabilization and nuclear localization is a hallmark ofβ-catenin/TCF pathway. (β-catenin/TCF pathway is abnormally activated in various tumors. It has been demonstrated that STAT3 is a novel target ofβ-catenin/TCF pathway in human esophageal squamous cell carcinoma and the gene encoding oncogenic miR-21 is controlled by an upstream enhancer containing STAT3 binding sites strictly conserved. We therefore searched for the mechanisms through whichβ-catenin/STAT3 may induce invasive growth in glioma cells.Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT family which participates in normal cellular responses to cytokines and growth factors as transcription factors. STAT3 participates in cellular transformation and oncogenesis. STAT3 is present in the cytoplasm under basal conditions. Phosphorylated STAT3s dimerize and translocate to the nucleus, where they regulate target gene transcription. Its activation is essential for the transforming potential of many oncogenes. By regulating target genes, STAT3 modulates various physiological functions including cell-cycle regulation, cell survival and angiogenesis.microRNAs (miRNA) are single-stranded RNA molecules that could mediate posttranscriptional down-regulation of target genes. They have been identified in the progression of various cancers and proposed as novel targets for anticancer therapies. Recent evidence indicates that miRNAs can function as both tumor suppressors and oncogenes. Using high-throughput miRNA profile and qRT-PCR, we have previously identified a specific miRNA. miRNA 21 (miR-21). as most strongly elevated in six glioma cell lines. Other groups also demonstrated overexpression of this miRNA in a wide range of other cancers. miR-21 has been identified as a possible oncogene controlling apoptosis, cell proliferation, and migration of cell lines in brain, breast, colorectal, and other cancers. Our previous study confirmed that downregulation of miR-21 inhibited the EGFR pathway and the anti-GBM effectis independent of PTEN status, suggesting that miR-21 was a broader therapeutic target for glioma.In the present study, we demonstrated thatβ-catenin signaling pathway regulated the expression of miR-21 via STAT3 in human gliomas, which strongly activate glioma cell invasion. P-catenin induces miR-21 expression and promoter activity through STAT3. The knockdown of miR-21 suppressedβ-catenin-induced cell invasion in glioma cells. Further, the up-regulation of miR-21 by p-catenin/STAT3 reduced RECK in gastric epithelial cells. These results indicate that miR-21 may play an important role inβ-catenin-promoted cell invasion by targeting RECK, providing a potential therapeutic target for gliomas.