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Published on: April 6, 2012
The regulation and function of miR-21-FOXO3a-miR-34b/c signaling in breast cancer
Xiangyan Liu1,2, Jie Feng3, Lili Tang2
1Department of General Surgery, the Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha 410013, China. lilitang474@yahoo.com.
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.
Insights
microRNA-21 (miR-21) and microRNA-34b/c (miR-34b/c) levels are altered in breast cancer (BC). This study reveals miR-21 promotes BC growth by downregulating miR-34b/c, suggesting therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Breast cancer (BC) is characterized by altered microRNA (miRNA) expression, specifically upregulation of miR-21 and downregulation of miR-34b/c.
- The precise regulatory mechanisms and functional roles of these miRNAs in BC progression remain incompletely understood.
Purpose of the Study:
- To elucidate the regulatory relationship between miR-21 and miR-34b/c in breast cancer.
- To investigate the functional impact of this relationship on cancer cell signaling and tumor growth.
- To evaluate the diagnostic and therapeutic potential of these miRNAs in BC.
Main Methods:
- Correlation analysis of miR-21 and miR-34b/c levels in BC samples.
- Investigation of the PTEN/PI3K/AKT signaling pathway and FOXO3a transcription factor activity.
- Analysis of miRNA expression in serum from BC patients.
- In vivo studies using systemic delivery of miRNAs to assess therapeutic efficacy.
Main Results:
- A significant inverse correlation between miR-21 and miR-34b/c levels was observed in BC.
- miR-21 upregulation leads to PTEN downregulation, activating PI3K/AKT signaling and inhibiting nuclear FOXO3a, a key regulator of miR-34b/c expression.
- Circulating miR-21 and miR-34b/c levels in serum show potential as BC biomarkers.
- Systemic delivery of miR-34b/c, with or without anti-miR-21, effectively inhibited breast tumor growth in vivo.
Conclusions:
- The findings establish a novel regulatory axis where miR-21 suppresses miR-34b/c expression via the PTEN/PI3K/AKT/FOXO3a pathway in breast cancer.
- Circulating miR-21 and miR-34b/c levels may serve as valuable biomarkers for BC diagnosis.
- Systemic administration of miR-34b/c presents a promising therapeutic strategy for breast cancer treatment.
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