Title

Kruppel-like factor 8 promotes tumorigenic mammary stem cell induction by targeting miR-146a

Authors

Authors

X. H. Wang; H. Lu; T. S. Li; L. Yu; G. Liu; X. Peng;J. H. Zhao

Comments

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Abbreviated Journal Title

Am. J. Cancer Res.

Keywords

KLF8; miR-146a; EMT; mammary stem cells; tumorigenesis; EPITHELIAL-MESENCHYMAL TRANSITION; FOCAL ADHESION KINASE; BREAST-CANCER; CELLS; MIR-200 FAMILY; HEPATOCELLULAR-CARCINOMA; UP-REGULATION; PANCREATIC-CANCER; MICRORNA MIR-146A; SIGNALING PATHWAYS; KLF8; TRANSCRIPTION; Oncology

Abstract

The properties of stem cells can be induced during the epithelial to mesenchymal transition (EMT). The responsible molecular mechanisms, however, remain largely undefined. Here we report the identification of the microRNA-146a (miR-146a) as a common target of Kruppel-like factor 8 (KLF8) and TGF-beta, both of which are known EMT-inducers. Upon KLF8 overexpression or TGF-beta treatment, a significant portion of the MCF-10A cells gained stem cell traits as demonstrated by an increased expression of CD44(high)/CD24(low), activity of aldehyde dehydrogenase (ALDH), mammosphere formation and chemoresistance. Along with this change, the expression of miR-146a was highly upregulated in the cells. Importantly, we found that miR-146a was aberrantly co-overexpressed with KLF8 in a panel of invasive human breast cancer cell lines. Ectopic expression of KLF8 failed to induce the stem cell traits in the MCF-10A cells if the cells were pre-treated with miR-146a inhibitor, whereas overexpression of miR-146a in the MCF-10A cells alone was sufficient to induce the stem cell traits. Co-staining and luciferase reporter analyses indicated that miR-146a targets the 3'-UTR of the Notch signaling inhibitor NUMB for translational inhibition. Overexpression of KLF8 dramatically potentiated the tumorigenecity of MCF-10A cells expressing the H-Ras oncogene, which was accompanied by a loss of NUMB expression in the tumors. Taken together, this study identifies a novel role and mechanism for KLF8 in inducing pro-tumorigenic mammary stem cells via miR-146a potentially by activating Notch signaling. This mechanism could be exploited as a therapeutic target against drug resistance of breast cancer.

Journal Title

American Journal of Cancer Research

Volume

3

Issue/Number

4

Publication Date

1-1-2013

Document Type

Article

Language

English

First Page

356

Last Page

373

WOS Identifier

WOS:000331069400003

ISSN

2156-6976

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