Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 16, Pages 10973-10985Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.434340
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Funding
- 973 Projects from the Ministry of Science and Technology of China [2010CB912800, 2011CB504203]
- National Science Foundation of China [81230060, 81261140373, 81072176, 81072177, 30800486]
- Foundation of Ministry of Education of the People's Republic of China [20120171110075]
- Science Foundation of Guangdong Province [S2012030006287]
- China Postdoctoral Science Foundation [201003379, 201104379]
- Guangdong Natural Science Foundation [10151503102000019]
- Science and Technology Foundation of the Guangdong Province [2008B030301238, 2008B030301243]
- National S&T Major Special Project on New Drug Innovation of China [2011ZX09102-010-02]
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MicroRNAs are involved in regulating the biology of cancer cells, but their involvement in chemoresistance is not fully understood. We found that miR-663 was up-regulated in our induced multidrug-resistant MDA-MB-231/ADM cell line and that this up-regulation was closely related to chemosensitivity. In the present study, we aimed to clarify the role of miR-663 in regulating the chemoresistance of breast cancer. MicroRNA microarray and quantitative RT-PCR assays were used to identify differentially expressed microRNAs. Cell apoptosis was evaluated by annexin V/propidium iodide staining, TUNEL, and reactive oxygen species generation analysis. The expression of miR-663 and HSPG2 in breast cancer tissues was detected by in situ hybridization and immunohistochemistry. The potential targets of miR-663 were defined by a luciferase reporter assay. Bisulfite sequencing PCR was used to analyze the methylation status. We found that miR-663 was significantly elevated in MDA-MB-231/ADM cells, and the down-regulation of miR-663 sensitized MDA-MB-231/ADM cells to both cyclophosphamide and docetaxel. The overexpression of miR-663 in breast tumor tissues was associated with chemoresistance; in MDA-MB-231 cells, this chemoresistance was accompanied by the down-regulation of HSPG2, which was identified as a target of miR-663. MDA-MB-231/ADM contained fewer methylated CpG sites than its parental cell line, and miR-663 expression in MDA-MB-231 cells was reactivated by 5-aza-29-deoxycytidine treatment, indicating that DNA methylation may play a functional role in the expression of miR-663. Our findings suggest that the over-expression of hypomethylated miR-663 induced chemoresistance in breast cancer cells by down-regulating HSPG2, thus providing a potential target for the development of an microRNA-based approach for breast cancer therapy.
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