Invasiveness and anchorage independent growth ability augmented by PTEN inactivation through the PI3K/AKT/NFkB pathway in lung cancer cells

Akça, Hakan; Demiray, Aydın; Tokgün, Onur; Yokota, Jun

doi:10.1016/j.lungcan.2011.01.012

Cited by 62 publications

(44 citation statements)

References 39 publications

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“…It has been reported that loss of function or downregulation of PTEN resulted in tumor metastasis, and more aggressive growth behaviors of tumor, and/or poor prognostic phenotypes. 42,[49][50][51][52][53][54][55][56][57] In addition, miR-19 upregulation was observed in various cancers including lung cancer, and correlated with tumor metastasis and/or poor prognosis of cancer patients. [11][12][13][14][15]18 Given that miRNAs primarily function through inhibiting the translation of their mRNA targets, we propose that miR-19 might be a negative regulator for PTEN, which has been reported by other researchers.…”

Section: Discussionmentioning

confidence: 99%

“…Increasing evidence supports that inactivation or downregulation of the tumor suppressor PTEN can trigger EMT of cancer cells, [60][61][62][63] which then promoted the invasion and metastasis of various cancers including lung cancer. 42,[49][50][51][52][53][54][55][56][57] It has been reported that PTEN negatively regulated the PI3K/ Akt pathway through the dephosphorylation of PI(3,4,5)P3, and ultimately participated in the regulation of cell cycle, proliferation, apoptosis, adhesion, and EMT during cancer progress. 63 In the present study, we found that PTEN silence through RNA interference mimicked miR-19-induced EMT, and promoted the migration and invasion of tumor cells, which were similar as the results caused by miR-19 overexpression.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA-19 triggers epithelial–mesenchymal transition of lung cancer cells accompanied by growth inhibition

Yang

Yan

et al. 2015

Laboratory Investigation

103

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The miR-19 family (miR-19a and miR-19b-1) are key oncogenic components of the miR-17-92 cluster. Overexpression of miR-19 is strongly associated with cancer invasion and metastasis, and poor prognosis of cancer patients. However, the underlying mechanisms remain largely unknown. In the present study, we found that enforced expression of miR-19 including miR-19a and miR-19b-1 triggered epithelial-mesenchymal transition (EMT) of lung cancer cells A549 and HCC827 as shown by mesenchymal-like morphological conversion, downregulation of epithelial proteins (e.g., E-cadherin, ZO-1 (zona occludens 1), and α-catenin), upregulation of mesenchymal proteins (e.g., vimentin, fibronectin 1, N-cadherin, and snail1), formation of stress fibers, and reduced cell adhesion. In addition, enhanced migration and invasion were observed in the cancer cells A549 and HCC827 undergoing EMT. In contrast, silencing of endogenous miR-19 reversed EMT and reduced the migration and invasion abilities of A549 and HCC827 cells. DNA microarray results revealed significant changes of the expression of genes related to EMT, migration, and metastasis of miR-19-expressing A549 cells. Moreover, siRNA-mediated knockdown of PTEN, a target of miR-19, also resulted in EMT, migration, and invasion of A549 and HCC827 cells, suggesting that PTEN is involved in miR-19-induced EMT, migration and invasion of lung cancer cells. Furthermore, lung cancer cells undergoing EMT induced by miR-19 demonstrated reduced proliferation in vitro and in vivo, and enhanced resistance to apoptosis caused by TNF-α. Taken together, these findings suggest that miR-19 triggers EMT, which has an important role in the invasion and migration of lung cancer cells, accompanied by the reduced proliferation of cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MicroRNA-19 triggers epithelial–mesenchymal transition of lung cancer cells accompanied by growth inhibition

Yang

Yan

et al. 2015

Laboratory Investigation

103

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“…Inactivation of PTEN often results in increased AKT activity in many types of tumors, including lung adenocarcinoma (Soria et al, 2002;Vivanco and Sawyers, 2002). The ectopic expression of PTEN in various tumor cell lines exerts inhibitory effects on several known biological actions of PI3K signaling pathway, for example, migration (Akca et al, 2011). In addressing how TOPK modulates the PI3K/ AKT pathway, we noticed that the protein expression level of PTEN was decreased in TOPK-WT-overexpressing cells as compared with vehicle and TOPK-KDtransfected cells (Figure 3b).…”

Section: Overexpression Of Topk Enhances Cell Migration and Invasion mentioning

confidence: 99%

TOPK/PBK promotes cell migration via modulation of the PI3K/PTEN/AKT pathway and is associated with poor prognosis in lung cancer

et al. 2011

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We integrated four gene expression profile data sets, namely two different pair-matched stage I lung adenocarcinoma data sets, secondary metastatic tumors vs benign tumors and lung tumor metastasizes to the brain, and we identified one kinase, T-LAK Cell-Originated Protein Kinase (TOPK), as a putative gene that promotes metastasis. To delineate the role of TOPK in lung cancer, we showed that overexpression of TOPK, but not a catalytically inactive form of TOPK, can enhance the migration and invasion of lung fibroblasts or cells with low TOPK expression. In addition, TOPK-induced cell migration was shown to be a PI3K/AKT-dependent event. TOPK concurrently promoted AKT phosphorylation at Ser 473 and decreased the phosphatase and tensin homolog (PTEN) levels, whereas TOPK knockdown had the reverse effects. LY294002, a PI3K inhibitor, did not inhibit the TOPK-induced decrease in PTEN, and coexpression of PTEN significantly reduced TOPK-induced AKT phosphorylation in a dose-dependent manner; these results indicate that the TOPK-mediated PTEN decrease has an upstream role in regulating PI3K/AKT-stimulated migration. Using immunohistochemical analysis of lung cancer tissue samples, we showed that a high TOPK expression level correlates strongly with reduced overall and disease-free survivals. Moreover, an inverse correlation between TOPK and PTEN expression was present and is consistent with the biochemical findings. Finally, a combination of high TOPK and low PTEN expression was inversely correlated with overall and disease-free survivals, independent of other pathologic staging factors. Our results suggest that TOPK is a potential therapeutic target in lung cancer that promotes cell migration by modulating a PI3K/PTEN/AKT-dependent signaling pathway; they also suggest that high TOPK expression, either alone or in combination with a low level of PTEN, may serve as a prognostic marker for lung cancer.

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“…PTENwt, lipidfosfatase dead PTEN G129E and kinase dead PTEN G129R were cloned in both, pcDNA3 and pcDNA6/TK expression vectors as described in our previous work 22 . By using FUGEN (Roche, Indianapolis, IN), PC14 cells were first stably transfected with regulatory plasmid pcDNA6/TK, and clones were selected by blasticidin (10 µg/ml).…”

Section: Expression Plasmids and Transfectionsmentioning

confidence: 99%

Tumour suppressor PTEN enhanced enzyme activity of GPx, SOD and catalase by suppression of PI3K/AKT pathway in non-small cell lung cancer cell lines

Akça

Demiray

Aslan

et al. 2012

Journal of Enzyme Inhibition and Medicinal Chemistry

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Invasiveness and anchorage independent growth ability augmented by PTEN inactivation through the PI3K/AKT/NFkB pathway in lung cancer cells

Cited by 62 publications

References 39 publications

MicroRNA-19 triggers epithelial–mesenchymal transition of lung cancer cells accompanied by growth inhibition

MicroRNA-19 triggers epithelial–mesenchymal transition of lung cancer cells accompanied by growth inhibition

TOPK/PBK promotes cell migration via modulation of the PI3K/PTEN/AKT pathway and is associated with poor prognosis in lung cancer

Tumour suppressor PTEN enhanced enzyme activity of GPx, SOD and catalase by suppression of PI3K/AKT pathway in non-small cell lung cancer cell lines

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