Abstract
We demonstrate that loss of succinate dehydrogenase 5 (SDH5) expression initiates epithelial-mesenchymal transition (EMT), which is visualized by the repression of E-cadherin and up-regulation of vimentin in lung cancer cell lines and clinical lung cancer specimens. In SDH5 knock-out mice, lung epithelial cells exhibited elevated mesenchymal markers, which is characteristic of EMT. Using a human lung xenograft-mouse model, we observed that knocking down endogenous SDH5 in human carcinoma cells leads to the development of multiple lymph node metastases. Moreover, our data indicate that SDH5 functions as a critical protein in regulating EMT by modulating the glycogen synthase kinase (GSK)-3β-β-catenin signaling pathway. These results reveal a critical role for SDH5 in EMT and suggest that SDH5 may be a prognostic biomarker and potential therapeutic target for lung cancer metastasis.
Keywords:
Biomarkers; E-cadherin; EMT; Lung Cancer; Metastasis; Mitochondrial Protein; SDH5.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Cell Line, Tumor
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Cell Movement
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Epithelial-Mesenchymal Transition
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism*
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Glycogen Synthase Kinase 3 beta
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Heterografts
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Humans
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Immunohistochemistry
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology*
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Male
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Mice
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Mice, Knockout
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Mice, Nude
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Microscopy, Confocal
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism*
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Neoplasm Metastasis
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Protein Binding
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Protein Phosphatase 2 / genetics
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Protein Phosphatase 2 / metabolism
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RNA Interference
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Signal Transduction
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Succinate Dehydrogenase / genetics
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Succinate Dehydrogenase / metabolism*
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Tumor Burden
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beta Catenin / genetics
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beta Catenin / metabolism*
Substances
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Mitochondrial Proteins
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SDHAF2 protein, human
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beta Catenin
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Succinate Dehydrogenase
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Glycogen Synthase Kinase 3
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Protein Phosphatase 2