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Sci Rep. 2018 Sep 5;8(1):13291. doi: 10.1038/s41598-018-31516-0.

Malignant Transformation of Human Bronchial Epithelial Cells Induced by Arsenic through STAT3/miR-301a/SMAD4 Loop.

Author information

1
The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
2
Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, South China Normal University, Guangzhou, 510631, China.
3
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
4
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. liy2@ccf.org.
5
The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China. sciencema@hotmail.com.
6
Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, South China Normal University, Guangzhou, 510631, China. sciencema@hotmail.com.

Abstract

Arsenic is a well-known of human carcinogen and miR-301a is an oncogenic microRNA, which links to oncogenesis, however, little is understood about its contribution to arsenic-induced cellular transformation and tumorigenesis. Here, we investigated the role of miR-301a during arsenic-induced cellular transformation and tumor formation. miR-301a was found to be upregulated during arsenic-induced BEAS-2B transformation and the overexpression of miR-301a was dependent on IL-6/STAT3 signaling. Inhibition of miR-301a leads to reduction of cell proliferation, colony formation and cell migration. By using dual luciferase assay, SMAD4 was confirmed to be a direct target of miR-301a in BEAS-2B cells and upregulation of SMAD4 is involved the restraining cell growth and migration. In addition, reducing of miR-301a expression enhances doxorubicin-induced cellular apoptosis of transformed BEAS-2B through up-regulating SMAD4. Furthermore, we demonstrated that downregulation of miR-301a in BEAS-2B attenuates tumor growth in the xenograft model by targeting SMAD4. Of note, the level of miR-301a expression correlated inversely with SMAD4 expression in clinical specimens of human lung cancer. Our findings ascertain that miR-301a is an oncogenic miRNA, which targets SMAD4 to establish an essential mechanism for arsenic-induced carcinogenesis, IL-6/STAT3/miR-301a/SMAD4 signaling pathways.

PMID:
30185897
PMCID:
PMC6125593
DOI:
10.1038/s41598-018-31516-0
[Indexed for MEDLINE]
Free PMC Article

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