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Biomed Pharmacother. 2016 Apr;79:93-101. doi: 10.1016/j.biopha.2016.01.045. Epub 2016 Feb 17.

miR-221/222 enhance the tumorigenicity of human breast cancer stem cells via modulation of PTEN/Akt pathway.

Author information

1
Department of Clinical Medicine, Grade 2013, Dalian Medical University, No. 9 West Section, Lvshun Road, Dalian 116044, China.
2
Department of Pathology and Forensics, Dalian Medical University, No. 9 West Section, Lvshun Road, Dalian 116044, China.
3
Academic Affairs Department, Dalian Medical University, No. 9 West Section, Lvshun Road, Dalian 116044, China.
4
Department of Pathology and Forensics, Dalian Medical University, No. 9 West Section, Lvshun Road, Dalian 116044, China. Electronic address: yr0806@hotmail.com.

Abstract

BACKGROUND:

The miR-221/222 cluster has been discovered to function as oncogene in human malignancies including breast cancer. However, the role of miR-221/222 in the self-renewal of breast cancer stem cells (BCSCs) is not fully understood. In this study, we examined the impact and mechanism of miR-221/222 on the breast cancer cell viability, migration and invasion, and propagation of BCSCs.

METHODS:

Human breast cancer cell line MCF-7 was transfected with miR-221/222 mimics or inhibitors to overexpress or knock down miR-221/222 respectively using Lipofactamine 2000. The biological effects of miR-221 and miR-222 were then assessed by cell proliferation assay, colony formation assay and transwell chamber assays. CD44/CD24 staining and mammosphere formation assay were performed to evaluate the ability of BCSCs self-renewal. Potential target gene phosphatase and tensin homolog (PTEN) and its downstream effector, phosphorylated Akt (p-Akt) were identified by Western blot and qRT-PCR methods.

RESULTS:

PTEN, a tumor suppressor gene, was confirmed as a target of miR-221/222 in breast cancer cell line MCF-7. Downregulation of PTEN by miR-221/222 increased the phosphorylation of Akt. Enforced expression of miR-221/222 promoted breast cancer cell proliferation, migration and invasion via targeting PTEN/Akt pathway. Importantly, ectopic expression of miR-221/222 enriched the proportion of CD44(+)/CD24(-) BCSCs and improved the mammosphere formation capacity through targeting PTEN/Akt pathway. Blocking the endogenous miR-221/222 restored PTEN expression and subsequently decreased Akt phosphorylation, and thereby reversed this phenotype.

CONCLUSIONS:

Our results suggested that miR-221/222 enhance breast cancer growth, migration and invasion, meanwhile propagate the self-renewal of BCSCs. This is achieved possibly through targeting PTEN/Akt pathway. miR-221/222 might be a novel therapeutic candidate for human breast cancer.

KEYWORDS:

Breast cancer; Cancer stem cell; PTEN/Akt pathway; microRNA-221/222

PMID:
27044817
DOI:
10.1016/j.biopha.2016.01.045
[Indexed for MEDLINE]

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