Abstract
Rictor upregulation and mTORC complex 2 (mTORC2) over-activation participate in glioma cell progression, yet the underling mechanisms are not known. We here identified microRNA-153 (miR-153) as a potential anti-Rictor miRNA, which was downregulated in multiple human glioma tissues and glioma cell lines (U87MG, T98G, U373MG and U251MG). miR-153 downregulation was correlated with Rictor (mRNA and protein) upregulation and p-Akt Ser473 (the mTORC2 indicator) over-activation in the glioma tissues and cells. Our in vitro evidences suggested that Rictor could be one primary target of miR-153 in glioma cells. Exogenous overexpression of miR-153 downregulated Rictor (mRNA and protein) and decreased p-Akt Ser473 in U87MG cells, leading to significant growth inhibition and apoptosis activation. Notably, U87MG cells with Rictor shRNA knockdown showed similar phenotypes of cells with miR-153 overexpression. More importantly, in Rictor-silenced U87MG cells, miR-153 expression failed to further affect cell growth nor apoptosis. In vivo, we showed that miR-153 overexpression dramatically inhibited U87MG tumor growth in nude mice. Together, these results suggest that miR-153 downregulation could be one important reason of Rictor upregulation and mTORC2 over-activation in glioma cells. Further, miR-153-induced anti-glioma cell activity is possibly via downregulating Rictor.
Highlights
glioma tissues (Glioma) causes large mortality around the world each year [1,2,3]
These results suggest that miR-153 downregulation could be one important reason of Rictor upregulation and mTOR complex 2 (mTORC2) over-activation in glioma cells
Mammalian target of rapamycin signaling is often dysregulated and hyper-activated in glioma, which mediates tumorigenesis, progression and chemoresistance [7,8,9]. mTOR lies in two distinct multi-protein mTOR complexes, including the traditional mTOR complex 1 and later-discovered rapamycin-insensitive mTOR complex 2 [10,11]. mTORC2 is composed of mTOR, Rictor, mSIN1, PLOS ONE | DOI:10.1371/journal.pone
Summary
Glioma causes large mortality around the world each year [1,2,3]. The prognosis for highgrade glioma (grade III-IV) has been poor [1,2,3]. Existing evidences have demonstrated that Rictor overexpression and mTORC2 over-activation promote glioma cell migration and proliferation [14,15]. MiRNAs are capable of regulating gene expression at both translational and post-transcriptional levels [16,17]. These 19–24 nucleotide single-stranded noncoding RNAs silence targeted mRNAs through partial complementarity in their 30 untranslated regions (UTRs) [16,17]. We identified a potential anti-Rictor miRNA: microRNA-153 (miR-153). Our results suggest that miR-153 downregulation could be the reason of Rictor upregulation and mTORC2 over-activation in human glioma cells. Overexpression of miR-153-induced anti-glioma cell activity is possibly via downregulating Rictor
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