Abstract
Radiotherapy is essential to treat breast cancer and microRNA (miRNA) miR-200c is considered as a radiosensitizer of breast cancer. However, the molecular mechanisms by which miR-200c regulates radiosensitivity remain largely unknown. In the present study, we showed that induction of miR-200c led to widespread alteration in long noncoding RNA (lncRNA) expression in breast cancer cells. We identified lncRNA LINC02582 as a target of miR-200c. Inhibition of LINC02582 expression increased radiosensitvity, while overexpression of LINC02582 promoted radioresistance. Mechanistically, LINC02582 interacts with deubiquitinating enzyme ubiquitin specific peptidase 7 (USP7) to deubiquitinate and stabilize checkpoint kinase 1 (CHK1), a critical effector kinase in DNA damage response, thus promoting radioresistance. Furthermore, we detected an inverse correlation between the expression of miR-200c vs. LINC02582 and CHK1 in breast cancer samples. These findings identified LINC02582 as a downstream target of miR-200c linking miR-200c to CHK1, in which miR-200c increases radiosensitivity by downregulation of CHK1.
Highlights
Radiation therapy plays an important role in the multidisciplinary management of breast cancer
LINC02582 is required for radioresistance in breast cancer cells
The results of the present study indicated that ectopic expression of miR-200c led to widespread alterations in long noncoding RNA (lncRNA) expression in breast cancer cells
Summary
Radiation therapy plays an important role in the multidisciplinary management of breast cancer. It provides local control and reduces tumor local relapse and increases patients’ long-term survival and decreases their mortality[1,2]. Radioresistance is a major cause of failure of breast cancer radiation therapy[3]. The molecular mechanisms involved in breast cancer radioresistance should be investigated. MiR-200c sensitizes breast cancer cells to radiation by targeting TBK1 and EGFR9,10. Our previous study showed that miR-200c sensitizes breast cancer cells to radiation by inhibiting radiation-induced autophagy[11]. MiR-200c acts as a tumor radiosensitizer and might represent an attractive target to increase the efficacy of radiation therapy for breast cancer. The molecular mechanisms by which miR-200c regulates radiosensitivity require further investigation
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