Down-regulation of lncRNA MEG3 promotes chronic low dose cadmium exposure-induced cell transformation and cancer stem cell-like property.
Toxicol Appl Pharmacol
; 430: 115724, 2021 11 01.
Article
en En
| MEDLINE
| ID: mdl-34520792
ABSTRACT
Cadmium (Cd) is a toxic heavy metal and one of carcinogens that cause lung cancer. However, the exact mechanism of Cd carcinogenesis remains unclear. To investigate the mechanism of Cd carcinogenesis, we exposed human bronchial epithelial cells (BEAS-2B) to a low dose of Cd (2.5 µM, CdCl2) for 9 months, which caused cell malignant transformation and generated cancer stem cell (CSC)-like cells. The goal of this study is to investigate the underlying mechanism. The long non-coding RNA (lncRNA) microarray analysis showed that the expression level of a tumor suppressive lncRNA maternally expressed 3 (MEG3) is significantly down-regulated in Cd-transformed cells, which is confirmed by further q-PCR analysis. Mechanistically, it was found that chronic Cd exposure up-regulates the levels of DNA methyltransferases (DNMTs), which increases the methylation of the differentially methylated region (DMR) 1.5 kb upstream of MEG3 transcription start site to reduce MEG3 expression. Functional studies showed that stably overexpressing MEG3 in Cd-transformed cells significantly reduces their transformed phenotypes. Moreover, stably overexpressing MEG3 in parental non-transformed human bronchial epithelial cells significantly impaired the capability of chronic Cd exposure to induce cell transformation and CSC-like property. Further mechanistic studies revealed that the cell cycle inhibitor p21 level is reduced and retinoblastoma protein (Rb) phosphorylation is increased in Cd-transformed cells to promote cell cycle progression. In addition, Cd-transformed cells also expressed higher levels of Bcl-xL and displayed apoptosis resistance. In contrast, stably overexpressing MEG3 increased p21 levels and reduced Rb phosphorylation and Bcl-xL levels in Cd-exposed cells and reduced their cell cycle progression and apoptosis resistance. Together, these findings suggest that MEG3 down-regulation may play important roles in Cd-induced cell transformation and CSC-like property by promoting cell cycle progression and apoptosis resistance.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Células Madre Neoplásicas
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Bronquios
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Transformación Celular Neoplásica
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Cloruro de Cadmio
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Células Epiteliales
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ARN Largo no Codificante
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Neoplasias Pulmonares
Límite:
Humans
Idioma:
En
Revista:
Toxicol Appl Pharmacol
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos