Abstract
Resistance to doxorubicin (DOX) is the most common clinical problem in breast cancer therapy, and the underlying molecular mechanism remains to be investigated. MicroRNAs (miRNAs) exhibit important regulatory functions in various malignant tumors including breast cancer. The aim of the present study was to find the relationship between miR-222 and DOX resistance. We found that miR-222 was highly expressed in patients’ serum and DOX-resistant cell line MCF-7-R and that miR-222 could promote proliferation and migration of breast cancer cells. Our results also showed that inhibition of miR-222 in MCF-7-R significantly increased Bcl-2 interacting mediator (Bim) expression both in mRNA and protein levels by using quantitative real-time PCR (qRT-PCR) and Western blot. MTT and flow cytometry suggested that lower expressed miR-222 enhanced apoptosis and decreased IC50 of MCF-7-R cells. Conversely, in MCF-7 cells transfected with miR-222 mimics, up-regulation of miR-222 was associated with decreased Bim level accompanied by less apoptosis and higher IC50. Moreover, miR-222 inhibitors reversed DOX resistance via miR-222-Bim-caspase pathway. Collectively, these data first elucidated that miR-222 could function as an oncogene and was able to reduce the sensitivity of breast cancer cells to DOX through miR-222-Bim-caspase pathway, which provided a potential target to increase DOX sensitivity in clinical breast cancer treatment.
Highlights
Breast cancer is considered as the most common malignant tumor among women worldwide [1]
MiR-222 was suggested as a tumor promoter in breast cancer cells and may be associated with DOX resistance in MCF-7
In order to figure out the function of miR-222 in breast cancer progression, we transfected miR-222 mimics or inhibitors to change the level of miR-222 in MCF-7 cells
Summary
Breast cancer is considered as the most common malignant tumor among women worldwide [1]. Chemotherapy is a crucial option for those patients in late stage. Patients rapidly get drug resistance to chemotherapy, which leads to a high incidence of early relapse [2]. Doxorubicin (DOX) is an extensively used anti-tumor agent in multifarious cancer treatment including breast cancer. The cardiotoxicity, low-selectivity, and drug resistance of DOX limited its extended application [3,4]. Reversing DOX chemoresistance needs more efforts to make
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