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Int J Mol Sci. 2015 Jan 30;16(2):3148-62. doi: 10.3390/ijms16023148.

The regulation and function of miR-21-FOXO3a-miR-34b/c signaling in breast cancer.

Author information

1
Department of General Surgery, the Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha 410013, China. lilitang474@yahoo.com.
2
Department of Breast Surgery, the Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha 410013, China. lilitang474@yahoo.com.
3
Department of Nursing, Thomas Jefferson University, Philadelphia, PA 19107, USA. jie.feng@jefferson.edu.
4
Department of General Surgery, the Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha 410013, China. musicjie302@yahoo.com.
5
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. qxwelcome@gmail.com.
6
Department of General Surgery, the Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha 410013, China. zhushaihong@medmail.com.cn.

Abstract

Upregulation of miR-21 (microRNA-21) and downregulation of miR-34b/c have been found in breast cancer (BC). However, their regulation mechanism and function roles in BC have not been fully addressed. Here, we report that miR-21 levels were inversely correlated with miR-34b/c levels in BC. MiR-21 upregulation contributes to PTEN downregulation, which is beneficial for the activation of PI3K/AKT signaling. The activation of AKT phosphorylates FOXO3a, triggering relocalization of FOXO3a proteins from the nucleus to the cytoplasm. FOXO3a is a newly identified transcription factor responsible for miR-34b/c expression. Downregulation of nuclear FOXO3a decreased the expression levels of miR-34b and miR-34c in breast cancer cells, in which p53 was mutated. We also found upregulation of circulating miR-21 and downregulation of circulating miR-34b/c in BC patients' serum. More importantly, we showed that systemic delivery of miR-34b/c or with anti-miR-21 significantly inhibited breast tumor growth in vivo. These results suggest that high circulating levels of miR-21 and low levels of miR-34b/c may provide potential biomarkers for BC diagnosis, and systemic delivery of miR-34b/c has potential as a therapeutic option for BC treatment.

PMID:
25647415
PMCID:
PMC4346885
DOI:
10.3390/ijms16023148
[Indexed for MEDLINE]
Free PMC Article

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