circRNA_0025202 Regulates Tamoxifen Sensitivity and Tumor Progression via Regulating the miR-182-5p/FOXO3a Axis in Breast Cancer.

Abstract

Tamoxifen is the most commonly used endocrine therapy for patients with hormone receptor (HR)-positive breast cancer. Despite its initial therapeutic efficacy, many patients eventually develop drug resistance, which remains a serious clinical challenge. To investigate roles of circular RNAs (circRNAs) in tamoxifen resistance, a tamoxifen-resistant MCF-7 cell line was established and screened for its circRNA expression profile by RNA sequencing. hsa_circ_0025202, a circRNA that was significantly downregulated, was selected for further investigation. Using a large cohort of clinical specimens, we found that hsa_circ_0025202 exhibited low expression in cancer tissues and was negatively correlated with lymphatic metastasis and histological grade. Gain- and loss-of-function assays indicated that hsa_circ_0025202 could inhibit cell proliferation, colony formation, and migration and increase cell apoptosis and sensitivity to tamoxifen. Bioinformatics and luciferase reporter assays verified that hsa_circ_0025202 could act as a miRNA sponge for miR-182-5p and further regulate the expression and activity of FOXO3a. Functional studies revealed that tumor inhibition and tamoxifen sensitization effects of hsa_circ_0025202 were achieved via the miR-182-5p/FOXO3a axis. Moreover, in vivo experiments confirmed that hsa_circ_0025202 could suppress tumor growth and enhance tamoxifen efficacy. Taken together, hsa_circ_0025202 served an anti-oncogenic role in HR-positive breast cancer, and it could be exploited as a novel marker for tamoxifen-resistant breast cancer.

• Authors: Yuting Sang, Bing Chen, Xiaojin Song, Yaming Li, Yiran Liang, Dianwen Han, Ning Zhang, Hanwen Zhang, Ying Liu, Tong Chen, Chen Li, Lijuan Wang, Wenjing Zhao, Qifeng Yang
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 27 Issue 9 Pg. 1638-1652 (09 04 2019) ISSN: 1525-0024 [Electronic] United States
• PMID: 31153828 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• 3' Untranslated Regions
• Biomarkers, Tumor
• FOXP3 protein, human
• Forkhead Transcription Factors
• MicroRNAs
• Mirn182 microRNA, human
• RNA, Circular
• Tamoxifen

Topics

• 3' Untranslated Regions
• Adult
• Aged
• Animals
• Apoptosis (genetics)
• Biomarkers, Tumor
• Breast Neoplasms (genetics, pathology)
• Cell Line, Tumor
• Cell Movement (genetics)
• Disease Models, Animal
• Disease Progression
• Drug Resistance, Neoplasm (genetics)
• Female
• Forkhead Transcription Factors (genetics)
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Heterografts
• Humans
• Mice
• MicroRNAs (genetics)
• Middle Aged
• Neoplasm Staging
• RNA Interference
• RNA, Circular (genetics)
• Tamoxifen (pharmacology)