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miR-93 promotes cell proliferation in gliomas through activation of PI3K/Akt signaling pathway.

Jiang L, Wang C, Lei F, Zhang L, Zhang X, Liu A, Wu G, Zhu J, Song L - Oncotarget (2015)

Bottom Line: 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.Furthermore, we found that overexpressing miR-93 promoted, but inhibition of miR-93 reduced, glioma cell proliferation and cell-cycle progression.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathophysiology, Guangzhou Medical University, Guangzhou 510182, China.

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.

No MeSH data available.


Related in: MedlinePlus

miR-93 promotes cell proliferation and cell-cycle progression in glioma cells(A) Representative micrographs (left) and quantification (right) of colonies formed by indicated glioma cell lines are shown 10 days after inoculation. (B) Effects of ectopic miR-93 on the tumorigenicity of the indicated glioma cell lines, as determined by anchorage-independent growth ability assay. (C) Representative micrographs (left) and quantification (right) of BrdUrd incorporating-cells of indicated glioma cells. (D) Effects of miR-93 overexpression on the cell cycle progression of glioma cells measured by flow cytometric analysis. Experiments were repeated at least 3 times with similar results, and error bars represent ± SD. *P < 0.05.
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Figure 2: miR-93 promotes cell proliferation and cell-cycle progression in glioma cells(A) Representative micrographs (left) and quantification (right) of colonies formed by indicated glioma cell lines are shown 10 days after inoculation. (B) Effects of ectopic miR-93 on the tumorigenicity of the indicated glioma cell lines, as determined by anchorage-independent growth ability assay. (C) Representative micrographs (left) and quantification (right) of BrdUrd incorporating-cells of indicated glioma cells. (D) Effects of miR-93 overexpression on the cell cycle progression of glioma cells measured by flow cytometric analysis. Experiments were repeated at least 3 times with similar results, and error bars represent ± SD. *P < 0.05.

Mentions: To investigate the biological function of miR-93 in the development and progression of glioma, glioma cells LN18 and Hs683 stably expressing miR-93 were established for the further study (Supplementary Figure 1). The result of colony formation assay revealed that ectopically expressing miR-93 in both LN18 and Hs683 cells markedly enhanced their growth ability, as indicated by the increase in colony numbers and sizes (Figure 2A). Consistently, an anchorage-independent growth assay revealed that miR-93-overexpressing LN18 and Hs683 cells formed more and larger-sized colonies than control cells (Figure 2B). Furthermore, the level of DNA synthesis, examined with BrdUrd incorporation assay, was significantly elevated in miR-93 transduced glioma cells, whereas the vector control cells displayed relatively lower BrdUrd incorporation rates (Figure 2C). Moreover, cell cycle analysis showed significant increases in the percentages of cells in the S peak while decreased percentages of cells in the G1/G0 peak (Figure 2D). Collectively, these results demonstrate that miR-93 functions to enhance proliferation, tumorigenicity and cell cycle progression of glioma cells.


miR-93 promotes cell proliferation in gliomas through activation of PI3K/Akt signaling pathway.

Jiang L, Wang C, Lei F, Zhang L, Zhang X, Liu A, Wu G, Zhu J, Song L - Oncotarget (2015)

miR-93 promotes cell proliferation and cell-cycle progression in glioma cells(A) Representative micrographs (left) and quantification (right) of colonies formed by indicated glioma cell lines are shown 10 days after inoculation. (B) Effects of ectopic miR-93 on the tumorigenicity of the indicated glioma cell lines, as determined by anchorage-independent growth ability assay. (C) Representative micrographs (left) and quantification (right) of BrdUrd incorporating-cells of indicated glioma cells. (D) Effects of miR-93 overexpression on the cell cycle progression of glioma cells measured by flow cytometric analysis. Experiments were repeated at least 3 times with similar results, and error bars represent ± SD. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480752&req=5

Figure 2: miR-93 promotes cell proliferation and cell-cycle progression in glioma cells(A) Representative micrographs (left) and quantification (right) of colonies formed by indicated glioma cell lines are shown 10 days after inoculation. (B) Effects of ectopic miR-93 on the tumorigenicity of the indicated glioma cell lines, as determined by anchorage-independent growth ability assay. (C) Representative micrographs (left) and quantification (right) of BrdUrd incorporating-cells of indicated glioma cells. (D) Effects of miR-93 overexpression on the cell cycle progression of glioma cells measured by flow cytometric analysis. Experiments were repeated at least 3 times with similar results, and error bars represent ± SD. *P < 0.05.
Mentions: To investigate the biological function of miR-93 in the development and progression of glioma, glioma cells LN18 and Hs683 stably expressing miR-93 were established for the further study (Supplementary Figure 1). The result of colony formation assay revealed that ectopically expressing miR-93 in both LN18 and Hs683 cells markedly enhanced their growth ability, as indicated by the increase in colony numbers and sizes (Figure 2A). Consistently, an anchorage-independent growth assay revealed that miR-93-overexpressing LN18 and Hs683 cells formed more and larger-sized colonies than control cells (Figure 2B). Furthermore, the level of DNA synthesis, examined with BrdUrd incorporation assay, was significantly elevated in miR-93 transduced glioma cells, whereas the vector control cells displayed relatively lower BrdUrd incorporation rates (Figure 2C). Moreover, cell cycle analysis showed significant increases in the percentages of cells in the S peak while decreased percentages of cells in the G1/G0 peak (Figure 2D). Collectively, these results demonstrate that miR-93 functions to enhance proliferation, tumorigenicity and cell cycle progression of glioma cells.

Bottom Line: 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.Furthermore, we found that overexpressing miR-93 promoted, but inhibition of miR-93 reduced, glioma cell proliferation and cell-cycle progression.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathophysiology, Guangzhou Medical University, Guangzhou 510182, China.

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.

No MeSH data available.


Related in: MedlinePlus