Inhibition of Chk1 by miR-320c increases oxaliplatin responsiveness in triple-negative breast cancer

Checkpoint kinase 1 (Chk1) expression is enhanced in most cancers owing to oncogenic activation and constant replicative stress. Chk1 inactivation is a promising cancer therapy, as its inactivation leads to genomic instability, chromosomal catastrophe, and cancer cell death. Herein, we observed that...

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Published in:Oncogenesis (New York, NY) Vol. 9; no. 10; p. 91
Main Authors: Lim, Sera, Kim, Yesol, Lee, Soo-Been, Kang, Hyeok-Gu, Kim, Da-Hyun, Park, Jee Won, Chung, Daeun, Kong, Hyunkyung, Yoo, Kyung Hyun, Kim, Yonghwan, Han, Wonshik, Chun, Kyung-Hee, Park, Jong Hoon
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 11-10-2020
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Summary:Checkpoint kinase 1 (Chk1) expression is enhanced in most cancers owing to oncogenic activation and constant replicative stress. Chk1 inactivation is a promising cancer therapy, as its inactivation leads to genomic instability, chromosomal catastrophe, and cancer cell death. Herein, we observed that miR-320c, downregulated in triple-negative breast cancer (TNBC) patients, can target Chk1. In addition, downregulated miR-320c expression was associated with poor overall survival in TNBC patients. As Chk1 was associated with the DNA damage response (DDR), we investigated the effect of miR-320c on DDR in TNBC cells. To induce DNA damage, we used platinum-based drugs, especially oxaliplatin, which is most effective with miR-320c. We observed that overexpression of miR-320c in TNBC regulated the oxaliplatin responsiveness by mediating DNA damage repair through the negative regulation of Chk1 in vitro. Furthermore, using a xenograft model, a combination of miR-320c mimic and oxaliplatin effectively inhibited tumor progression. These investigations indicate the potential of miR-320c as a marker of oxaliplatin responsiveness and a therapeutic target to increase the efficacy of chemotherapy in TNBC.
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ISSN:2157-9024
2157-9024
DOI:10.1038/s41389-020-00275-x