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

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.

• Authors: Chun-Wen Cheng, Jyh-Cherng Yu, Yi-Hsien Hsieh, Wen-Ling Liao, Jia-Ching Shieh, Chung-Chin Yao, Huei-Jane Lee, Po-Ming Chen, Pei-Ei Wu, Chen-Yang Shen
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 48 Issue 5 Pg. 2205-2218 ( 2018) ISSN: 1421-9778 [Electronic] Germany
• PMID: 30110679 (Publication Type: Journal Article)
• Copyright: © 2018 The Author(s). Published by S. Karger AG, Basel.

Chemical References

• AC133 Antigen
• Antagomirs
• MIRN221 microRNA, human
• MIRN92 microRNA, human
• MicroRNAs
• Nanog Homeobox Protein

Topics

• AC133 Antigen (metabolism)
• Adult
• Antagomirs (metabolism)
• Area Under Curve
• Breast Neoplasms (diagnosis, genetics, mortality, pathology)
• Cell Line, Tumor
• Cell Movement
• Female
• Humans
• Lymphatic Metastasis
• MCF-7 Cells
• MicroRNAs (antagonists & inhibitors, genetics, metabolism)
• Middle Aged
• Nanog Homeobox Protein (metabolism)
• Neoplastic Stem Cells (cytology, metabolism)
• Prognosis
• Proportional Hazards Models
• ROC Curve
• Survival Rate