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Chronic TGF beta stimulation promotes the metastatic potential of lung cancer cells by Snail protein stabilization through integrin beta 3-Akt-GSK3 beta signaling

Title
Chronic TGF beta stimulation promotes the metastatic potential of lung cancer cells by Snail protein stabilization through integrin beta 3-Akt-GSK3 beta signaling
Author(s)
Bae, Gab-YongHong, Soon-KiPark, Jeong-RakKwon, Ok-SeonKim, Keun-TaeKoo, JaeHyungOh, EnselCha, Hyuk-Jin
Issued Date
2016-05
Citation
Oncotarget, v.7, no.18, pp.25366 - 25376
Type
Article
Author Keywords
chronic TGF beta exposureintegrin beta 3AktGSK3 betaSnail
Keywords
A549 Cell LineAKTArticleBeta3 IntegrinGlycogen Synthase Kinase-3 BetaGSK-3 BetaHumanIntegrin Beta 3InvasionCancer PrognosisCell InvasionCell MigrationChronic TGF Beta ExposureCLINICAL-TRIALSControlled StudyDOWN-REGULATIONEPITHELIAL-CELLSEXPRESSIONGene ExpressionLong Term ExposureLung AdenocarcinomaLung Cancer Cell LineMajor Clinical StudyMessenger RNAMetastasis PotentialOverall SurvivalPhosphorylationPROGRESSIONProtein Kinase BProtein PhosphorylationProtein StabilitySignal TransductionSMADSmad ProteinSnailTranscription Factor SnailTRANSFORMING-GROWTH-FACTORTransforming Growth Factor BetaTUMOR-SUPPRESSOR
ISSN
1949-2553
Abstract
Chronic exposure to TGFβ, a frequent occurrence for tumor cells in the tumor microenvironment, confers more aggressive phenotypes on cancer cells by promoting their invasion and migration while at the same time increasing their resistance to the growth-inhibitory effect of TGFβ. In this study, a transdifferentiated (TD) A549 cell model, established by chronically exposing A549 cells to TGFβ, showed highly invasive phenotypes in conjunction with attenuation of Smad-dependent signaling. We show that Snail protein, the mRNA expression of which strongly correlates with a poor prognosis in lung cancer patients, was highly stable in TD cells after TGFβ stimulation. The increased protein stability of Snail in TD cells correlated with elevated inhibitory phosphorylation of GSK3β, resulting from the high Akt activity. Notably, integrin β3, whose expression was markedly increased upon sustained exposure to TGFβ, was responsible for the high Akt activity as well as the increased Snail protein stability in TD cells. Consistently, clinical database analysis on lung cancer patients revealed a negative correlation between overall survival and integrin β3 mRNA levels. Therefore, we suggest that the integrin β3-Akt-GSK3β signaling axis plays an important role in non-canonical TGFβ signaling, determining the invasive properties of tumor cells chronically exposed to TGFβ.
URI
http://hdl.handle.net/20.500.11750/2541
DOI
10.18632/oncotarget.8295
Publisher
Impact Journals LLC
Related Researcher
  • 구재형 Koo, JaeHyung
  • Research Interests 장내미생물/감염균 유래 대사체를 통한 신경염증; 알츠하이머병; 우울증; 당뇨/비만; 대사체/수용체 상호작용에 의한 대사연구
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Department of New Biology Brain-Immune Axis Laboratory 1. Journal Articles

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