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Abstract
The PI3K/Akt signaling pathway is frequently activated in various human cancer types and plays essential roles in development and progression of cancers. Multiple regulators, such as phosphatase and tensin homolog (PTEN) and PH domain leucine rich repeat protein phosphatases (PHLPP), have also found to be involved in suppression of the PI3K/Akt signaling pathway. However, how suppressive effects mediated by these regulators are concomitantly disrupted in cancers, which display constitutively activated PI3K/Akt signaling, remains puzzling. In the present study, we reported that the expression of miR-93 was markedly upregulated in glioma cell lines and clinical glioma tissues. Statistical analysis revealed that miR-93 levels significantly correlated with clinicopathologic grade and overall survival in gliomas. Furthermore, we found that overexpressing miR-93 promoted, but inhibition of miR-93 reduced, glioma cell proliferation and cell-cycle progression. We demonstrated that miR-93 activated PI3K/Akt signaling through directly suppressing PTEN, PHLPP2 and FOXO3 expression via targeting their 3'UTRs. Therefore, our results suggest that miR-93 might play an important role in glioma progression and uncover a novel mechanism for constitutive PI3K/Akt activation in gliomas.
Highlights
The phosphatidylinositol-3-OH kinase (PI3K)-Akt pathway is a major signaling cascade that is activated in a large variety of human cancers [1]
We demonstrated that miR-93 activated PI3K/Akt signaling through directly suppressing phosphatase and tensin homolog (PTEN), PHLPP2 and FOXO3 expression via targeting their 3’ untranslated region (3′UTR)
Real-time PCR analysis revealed that miR-93 was significantly overexpressed in 10 freshly collected gliomas samples as compared with paired adjacent non-tumor tissues obtained from the same patient (Figure 1B), and 9 glioma cell lines compared with the normal human astrocytes (NHA) control (Figure 1C)
Summary
The phosphatidylinositol-3-OH kinase (PI3K)-Akt pathway is a major signaling cascade that is activated in a large variety of human cancers [1]. The phosphorylation of Akt activates downstream target genes involved in survival, proliferation, cell cycle progression, growth and migration of tumor cells, as well as angiogenesis [1,2,3,4, 6, 7]. Akt could phosphorylate and suppress the transcriptional factor FOXO3, leading to upregulation of Cyclin D1 and suppression of p27Kip that promote cell cycle progression and cell proliferation [8, 9]. PHLPP2, an isoform of PHLPP phosphatases, has been reported to induce cell cycle arrest and apoptosis and suppress tumor growth by directly dephosphorylating and inactivating of Akt at Ser473 and depressing the activity of PI3K/ Akt signaling pathway subsequently [20, 21]. Understanding the precise molecular mechanisms underlying regulation of negative regulators of PI3K/Akt signaling could provide new insights into the pathogenesis of cancers and lead to more effective anticancer therapy strategies
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