MiR-155 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells through the activation of PI3K/SGK3/β-catenin signaling pathways

Kong, Xin; Liu, Fengchao; Gao, Jian

doi:10.18632/oncotarget.11800

Cited by 27 publications

(17 citation statements)

References 36 publications

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“…Our previous study confirmed that SGK3 stimulates β-catenin signalling in HCC cells [ 23 ]. It is well established that SGK3 promotes the inactivation of GSK-3β by phosphorylation of GSK-3β on Ser9 [ 22 ].…”

Section: Resultssupporting

confidence: 82%

“…The augmentation of Wnt/β-catenin signalling through Ser9 phosphorylation-inactivation of GSK3β is a well-recognised regulatory pathway for CSC self-renewal and cancer development [ 35 , 36 ]. Our previous study confirmed that SGK3 stimulates β-catenin signalling in HCC cells [ 23 ]. Liu et al reported that overexpression of SGK3 increased the phosphorylation level of GSK3-β on Ser9 and inactivates GSK3-β [ 22 ].…”

Section: Discussionsupporting

confidence: 82%

“…Amplification and overexpression of SGK3 was frequently detected in HCC specimens, and SGK3 can promote HCC cell survival, proliferation and tumour formation in nude mice [ 22 ]. Our previous study found that SGK3 promotes HCC cell migration and invasive potential [ 23 ], which confirmed its vital function in promoting HCC progression. However, whether SGK3 also plays an important role in CSCs has not yet been reported.…”

Section: Discussionmentioning

confidence: 62%

“…Amplification and overexpression of SGK3 have been reported more frequently than those for AKT in HCC, suggesting it may have a greater functional significance in HCC [ 22 ]. Our previous study found that SGK3 plays an important role in the invasive potential of HCC cells and epithelial-mesenchymal transition (EMT) [ 23 ]. However, the role and mechanism of SGK3 in CSCs has not been reported.…”

Section: Introductionmentioning

confidence: 99%

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Prolonged inhibition of class I PI3K promotes liver cancer stem cell expansion by augmenting SGK3/GSK-3β/β-catenin signalling

Liu

Jiang

et al. 2018

J Exp Clin Cancer Res

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BackgroundSerum and glucocorticoid-regulated kinase 3 (SGK3) has been reported to play an important role in tumour progression, but its role in cancer stem cells (CSCs) remains obscure. The phosphoinositide 3-kinase (PI3K) pathway is considered a hallmark of cancer. Although many PI3K pathway-targeted therapies have been tested in oncology trials, the results are not satisfactory.MethodsWe used spheroids cultured in serum-free culture medium and MicroBead isolation to obtain liver CSCs. Spheroid formation assay and flow cytometric analysis were performed to investigate liver CSC expansion. Real-time polymerase chain reaction (PCR), western blot and immunofluorescence were used to assess gene expression in cell lines.ResultsWe found that SGK3 is preferentially activated in liver CSCs. Upregulated SGK3 significantly increases the expansion of liver CSCs. Conversely, suppression of SGK3 in human hepatocarcinoma (HCC) cells had an opposite effect. Mechanistically, SGK3 promoted β-catenin accumulation by suppressing GSK-3β-mediated β-catenin degradation in liver CSCs, and then promoting the expansion of liver CSCs. Prolonged treatment of HCC cells with class I PI3K inhibitors leads to activation of SGK3 and expansion of liver CSCs. Inhibition of hVps34 can block SGK3 activity and suppress liver CSC expansion induced by PI3K inhibitors. More importantly, we also found that prolonged treatment of HCC cells with PI3K inhibitors stimulates the β-catenin signalling pathway via activation of SGK3.ConclusionsProlonged inhibition of class I PI3K promotes liver CSC expansion by augmenting SGK3-dependent β-catenin stabilisation, and effective inhibition of SGK3 signalling may be useful in eliminating liver CSCs and in PI3K pathway-targeted cancer therapies.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0801-8) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 82%

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

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Prolonged inhibition of class I PI3K promotes liver cancer stem cell expansion by augmenting SGK3/GSK-3β/β-catenin signalling

Liu

Jiang

et al. 2018

J Exp Clin Cancer Res

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“…In addition, miR-155 has been reported to target other genes to regulate epithelial–mesenchymal transition (EMT) process. In hepatocellular carcinoma, miR-155 promotes EMT via targeting P85α and TP53INP1 [ 41 , 42 ]. In murine mammary gland epithelial cells, MiR-155 promotes TGF-β-induced EMT via targeting RhoA [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

The mechanism of TGF-β/miR-155/c-Ski regulates endothelial–mesenchymal transition in human coronary artery endothelial cells

Wang

et al. 2017

Bioscience Reports

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Human coronary artery endothelial cells (HCAECs) have the potential to undergo fibrogenic endothelial–mesenchymal transition (EndMT), which results in matrix-producing fibroblasts and thereby contributes to the pathogenesis of cardiac fibrosis. Recently, the profibrotic cytokine transforming growth factor-β (TGF-β) is shown to be the crucial pathogenic driver which has been verified to induce EndMT. C-Ski is an important regulator of TGF-β signaling. However, the detailed role of c-Ski and the molecular mechanisms by which c-Ski affects TGF-β-induced EndMT in HCAECs are not largely elucidated. In the present study, we treated HCAECs with TGF-β of different concentrations to induce EndMT. We found that overexpression of c-Ski in HCAECs either blocked EndMT via hindering Vimentin, Snail, Slug, and Twist expression while enhancing CD31 expression, with or without TGF-β treatment. In contrast, suppression of c-Ski further enhanced EndMT. Currently, miRNA expression disorder has been frequently reported associating with cardiac fibrosis. By using online tools, we regarded miR-155 as a candidate miRNA that could target c-Ski, which was verified using luciferase assays. C-Ski expression was negatively regulated by miR-155. TGF-β-induced EndMT was inhibited by miR-155 silence; the effect of TGF-β on Vimentin, CD31, Snail, Slug, and Twist could be partially restored by miR-155. Altogether, these findings will shed light on the role and mechanism by which miR-155 regulates TGF-β-induced HCAECs EndMT via c-Ski to affect cardiac fibrosis, and miR-155/c-Ski may represent novel biomarkers and therapeutic targets in the treatment of cardiac fibrosis.

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miR-155 inhibits oxidized low-density lipoprotein–induced apoptosis in different cell models by targeting the p85α/AKT pathway

Ruan

Chu

et al. 2020

J Physiol Biochem

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MiR-155 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells through the activation of PI3K/SGK3/β-catenin signaling pathways

Cited by 27 publications

References 36 publications

Prolonged inhibition of class I PI3K promotes liver cancer stem cell expansion by augmenting SGK3/GSK-3β/β-catenin signalling

Prolonged inhibition of class I PI3K promotes liver cancer stem cell expansion by augmenting SGK3/GSK-3β/β-catenin signalling

The mechanism of TGF-β/miR-155/c-Ski regulates endothelial–mesenchymal transition in human coronary artery endothelial cells

miR-155 inhibits oxidized low-density lipoprotein–induced apoptosis in different cell models by targeting the p85α/AKT pathway

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