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Histone deacetylase 1/Sp1/microRNA-200b signaling accounts for maintenance of cancer stem-like cells in human lung adenocarcinoma.

ABSTRACT: The presence of cancer stem-like cells (CSCs) is one of the mechanisms responsible for chemoresistance that has been a major hindrance towards lung adenocarcinoma (LAD) treatment. Recently, we have identified microRNA (miR)-200b as a key regulator of chemoresistance in human docetaxel-resistant LAD cells. However, whether miR-200b has effects on regulating CSCs remains largely unclear and needs to be further elucidated. Here, we showed that miR-200b was significantly downregulated in CD133+/CD326+ cells that exhibited properties of CSCs derived from docetaxel-resistant LAD cells. Also, restoration of miR-200b could inhibit maintenance and reverse chemoresistance of CSCs. Furthermore, suppressor of zeste-12 (Suz-12) was identified as a direct and functional target of miR-200b, and silencing of Suz-12 phenocopied the effects of miR-200b on CSCs. Additionally, overexpression of histone deacetylase (HDAC) 1 was identified as a pivotal mechanism responsible for miR-200b repression in CSCs through a specificity protein (Sp) 1-dependent mechanism, and restoration of miR-200b by HDAC1 repression significantly suppressed CSCs formation and reversed chemoresistance of CSCs by regulating Suz-12-E-cadherin signaling. Also, downregulation of HDAC1 or upregulation of miR-200b reduced the in vivo tumorigenicity of CSCs. Finally, Suz-12 was inversely correlated with miR-200b, positively correlated with HDAC1 and up-regulated in docetaxel-resistant LAD tissues compared with docetaxel-sensitive tissues. Taken together, the HDAC1/miR-200b/Suz-12-E-cadherin signaling might account for maintenance of CSCs and formation of chemoresistant phenotype in docetaxel-resistant LAD cells.

SUBMITTER: Chen DQ

PROVIDER: S-EPMC4184862 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Histone deacetylase 1/Sp1/microRNA-200b signaling accounts for maintenance of cancer stem-like cells in human lung adenocarcinoma.

Chen Dong-Qin DQ Huang Jia-Yuan JY Feng Bing B Pan Ban-Zhou BZ De Wei W Wang Rui R Chen Long-Bang LB

PloS one 20141003 10

The presence of cancer stem-like cells (CSCs) is one of the mechanisms responsible for chemoresistance that has been a major hindrance towards lung adenocarcinoma (LAD) treatment. Recently, we have identified microRNA (miR)-200b as a key regulator of chemoresistance in human docetaxel-resistant LAD cells. However, whether miR-200b has effects on regulating CSCs remains largely unclear and needs to be further elucidated. Here, we showed that miR-200b was significantly downregulated in CD133+/CD32 ...[more]

PMID: 25279705

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Project description:ObjectiveThe aim of this study was to investigate the microRNA-200b-3p expression in lung adenocarcinoma and the possible functional associations of microRNA-200b-3p with cell proliferation, migration, and invasion.MethodsQuantitative real-time polymerase chain reaction was used to detect the expression of microRNA-200b-3p in lung adenocarcinoma samples and in the human lung adenocarcinoma cell lines A549 and H1299. A549 and H1299 cells were transfected with either a microRNA-200b-3p mimic or a negative control microRNA or either an empty vector or an adenosine triphosphate-binding cassette transporter A-1 overexpression vector. A Cell Counting Kit-8 assay was employed to assess the ability of cell proliferation. Transwell assays and transwell-Matrigel invasion assay were, respectively, utilized to assess the capacity of migration and invasion in A549 and H1299 cells.ResultsThe results showed that microRNA-200b-3p expression was significantly upregulated in tumor tissues compared with that in adjacent normal tissues. Overexpression of microRNA-200b-3p promoted lung adenocarcinoma cell proliferation and metastasis. Furthermore, adenosine triphosphate-binding cassette transporter A-1 was a direct target of microRNA-200b-3p, and this binding was verified by luciferase reporter analysis. Overexpression of adenosine triphosphate-binding cassette transporter A-1 obviously suppressed lung adenocarcinoma cell proliferation, migration, and invasion. Lung adenocarcinoma cell phenotypes induced by microRNA-200b-3p overexpression could be partially remitted by the co-overexpression of microRNA-200b-3p and adenosine triphosphate-binding cassette transporter A-1.ConclusionThis study first identified that microRNA-200b-3p is upregulated in lung adenocarcinoma cells and associated with cell proliferation and metastasis. MicroRNA-200b-3p promoted lung adenocarcinoma cell proliferation and metastasis by suppressing adenosine triphosphate-binding cassette transporter A-1. MicroRNA-200b-3p may function as a novel molecular marker and therapeutic target for lung adenocarcinoma treatment.

Dataset Information

Histone deacetylase 1/Sp1/microRNA-200b signaling accounts for maintenance of cancer stem-like cells in human lung adenocarcinoma.

Publications

Histone deacetylase 1/Sp1/microRNA-200b signaling accounts for maintenance of cancer stem-like cells in human lung adenocarcinoma.

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