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Cell Physiol Biochem. 2018;48(5):2205-2218. doi: 10.1159/000492561. Epub 2018 Aug 15.

Increased Cellular Levels of MicroRNA-9 and MicroRNA-221 Correlate with Cancer Stemness and Predict Poor Outcome in Human Breast Cancer.

Author information

1
Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
2
Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan.
3
Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
4
Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.
5
Center for Personalized Medicine, China Medical University Hospital, Taichung, Taiwan.
6
Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan.
7
Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan.
8
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
9
College of Public Health, China Medical University, Taichung, Taiwan.

Abstract

Background /Aims: Recent studies of microRNA (miRNA) involvement in tumorigenesis have indicated the critical role of these non-coding small RNAs in malignant transformation, but the prognostic role, if any, of miRNAs in breast cancer remains undetermined. Therefore, we assessed the prognostic significance of microRNA-9 (miR-9) and miR-221 in breast cancer toward the goal of understanding the contribution(s) of these miRNAs to cancer cell stemness.

METHODS:

The level of each of miR-9 and miR-221 in 206 paired laser capture microdissected tumor cells and non-tumor cells was determined by quantitative reverse transcription-PCR (qRT-PCR). The relationship between the miRNA signature and clinicopathological data and prognosis of breast cancer was assessed. Identification of a stem cell-enriched side population was achieved with fluorescence-activated cell sorting and a sphere-forming assay. Wound healing, Boyden chamber assays, and western blotting were used to study the contribution of each miRNA to tumor cell migration and invasion.

RESULTS:

We found that induction of miR-9 and miR-221 mimics conferred side-population cells to form spheroidal tumor colonies in suspension culture that maintained the mesenchymal stem-cell potential in non-invasive MCF-7 breast cancer cells. In contrast, knockdown of both miR-9 and miR-221 in invasive MDA-MB-231 breast cancer cells dramatically decreased the number of side-population colonies with stem cell-like potency, which reduced the capacity for tumor-cell renewal, invasion, and migration. Clinically, the mean proportion of miR-9- or miR-221-overexpressing cells was significantly greater in tumor cells compared with non-tumor cells (P < 0.05). Increased levels of miR-9 and miR-221 in breast tissue portended a significantly elevated risk of progression to malignancy with respect to larger tumor size, poor differentiation, late-stage evolution, lymph-node metastasis (P < 0.05), and lower overall survival (Ptrend = 0.017; eight-year follow-up).

CONCLUSION:

Our findings provide strong evidence that miR-9 and miR-221 can enhance the generation of cancer stem cells to yield an invasive phenotype and that overexpression of these miRNAs predicts a poor outcome for breast cancer patients.

KEYWORDS:

Breast cancer; MiR-221; MiR-9; Prognosis; Stemness

PMID:
30110679
DOI:
10.1159/000492561
[Indexed for MEDLINE]
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