Long noncoding RNA LINC02582 acts downstream of miR-200c to promote radioresistance through CHK1 in breast cancer cells
Long noncoding RNA LINC02582 acts downstream of miR-200c to promote radioresistance through CHK1 in breast cancer cells
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长非编码 RNA LINC02582 作用于 miR-200c 下游，通过 CHK1 促进乳腺癌细胞的放射抗性
DOI：
10.1038/s41419-019-1996-0
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发表时间：
2019-10-10
影响因子：
9
通讯作者：
Yuan, Yawei
中科院分区：
文献类型：
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作者：
Wang, Baiyao;Zheng, Jieling;Yuan, Yawei
放射治疗是治疗乳腺癌的重要手段，microRNA（miRNA）miR-200 c被认为是乳腺癌的放射增敏剂。然而，miR-200 c调节放射敏感性的分子机制在很大程度上仍然未知。在本研究中，我们发现miR-200 c的诱导导致乳腺癌细胞中长链非编码RNA（lncRNA）表达的广泛改变。我们将lncRNA LINC 02582鉴定为miR-200 c的靶标。抑制LINC 02582表达增加了放射敏感性，而过表达LINC 02582促进了放射抗性。在机制上，LINC 02582与去泛素化酶泛素特异性肽酶7（USP 7）相互作用，以去泛素化和稳定检查点激酶1（CHK 1），这是DNA损伤反应中的关键效应激酶，从而促进辐射抗性。此外，我们在乳腺癌样本中检测到miR-200 c与LINC 02582和CHK 1的表达之间的负相关性。这些发现将LINC 02582确定为连接miR-200 c与CHK 1的miR-200 c下游靶点，其中miR-200 c通过下调CHK 1来增加放射敏感性。
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.