Essential role of aldehyde dehydrogenase 1A3 for the maintenance of non-small cell lung cancer stem cells is associated with the STAT3 pathway.
Clin Cancer Res
; 20(15): 4154-66, 2014 Aug 01.
Article
en En
| MEDLINE
| ID: mdl-24907115
ABSTRACT
PURPOSE:
Lung cancer stem cells (CSC) with elevated aldehyde dehydrogenase (ALDH) activity are self-renewing, clonogenic, and tumorigenic. The purpose of our study is to elucidate the mechanisms by which lung CSCs are regulated. EXPERIMENTALDESIGN:
A genome-wide gene expression analysis was performed to identify genes differentially expressed in the ALDH(+) versus ALDH - cells. RT-PCR, Western blot analysis, and Aldefluor assay were used to validate identified genes. To explore the function in CSCs, we manipulated their expression followed by colony and tumor formation assays.RESULTS:
We identified a subset of genes that were differentially expressed in common in ALDH(+) cells, among which ALDH1A3 was the most upregulated gene in ALDH(+) versus ALDH - cells. shRNA-mediated knockdown of ALDH1A3 in non-small cell lung cancer (NSCLC) resulted in a dramatic reduction in ALDH activity, clonogenicity, and tumorigenicity, indicating that ALDH1A3 is required for tumorigenic properties. In contrast, overexpression of ALDH1A3 by itself it was not sufficient to increase tumorigenicity. The ALDH(+) cells also expressed more activated STAT3 than ALDH - cells. Inhibition of STAT3 or its activator EZH2 genetically or pharmacologically diminished the level of ALDH(+) cells and clonogenicity. Unexpectedly, ALDH1A3 was highly expressed in female, never smokers, well-differentiated tumors, or adenocarcinoma. ALDH1A3 low expression was associated with poor overall survival.CONCLUSIONS:
Our data show that ALDH1A3 is the predominant ALDH isozyme responsible for ALDH activity and tumorigenicity in most NSCLCs, and that inhibiting either ALDH1A3 or the STAT3 pathway are potential therapeutic strategies to eliminate the ALDH(+) subpopulation in NSCLCs.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Células Madre Neoplásicas
/
Transducción de Señal
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Biomarcadores de Tumor
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Carcinoma de Pulmón de Células no Pequeñas
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Aldehído Oxidorreductasas
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Factor de Transcripción STAT3
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Neoplasias Pulmonares
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
2014
Tipo del documento:
Article