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

Abstract

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.

MicroRNA 320, an Anti-Oncogene Target miRNA for Cancer Therapy

“…The downregulation of miR-320 has been reported to be relevant to drug resistance to treatments such as oxaliplatin, epirubicin, gemcitabine, tamoxifen, and doxorubicin [ 34 , 77 , 85 , 86 , 87 , 88 , 89 ]. However, the drug resistance mechanisms utilized in these examples are not fully understood.…”

“…However, the drug resistance mechanisms utilized in these examples are not fully understood. Interestingly, some reports have found that the recovery of miR-320 expression can effectively alleviate drug resistance to certain drugs [ 34 , 77 , 88 ]. For example, Wan et al [ 34 , 63 ] reported that overexpression of miR-320 could elevate the sensitivity of CRC cells to 5-Fu and oxaliplatin by targeting forkhead box M1 (FOXM1) .…”

“…Moreover, the expression of hsa-miR-320a-3p was significantly negatively associated with anthracycline sensitivity. Lim et al [ 77 ] reported that recovery of hsa-miR-320c expression could increase the responsiveness to oxaliplatin in triple-negative breast cancer (TNBC) through targeting checkpoint kinase 1 (Chk1), which regulated DNA damage responses. When examining the miRNA expression of cells treated with gemcitabine-based chemotherapy, maladjustment of hsa-miR-320c was associated with an attenuated sensitivity to gemcitabine in pancreatic cancer [ 86 ].…”

Integrated study of miR‐215 promoting breast cancer cell apoptosis by targeting RAD54B

“…In different blood samples or solid tumour tissues, miRNAs show a high degree of specificity and are closely related to clinical aspects, such as the survival time of tumour patients, drug sensitivity and mRNA expression. A number of studies have found that miRNAs have an inevitable connection with the occurrence and development of BC 8‐10 . This indicates that miRNAs have important regulatory functions.…”

Circular RNA FAT atypical cadherin 1 (circFAT1)/microRNA-525-5p/spindle and kinetochore-associated complex subunit 1 (SKA1) axis regulates oxaliplatin resistance in breast cancer by activating the notch and Wnt signaling pathway

“…As a third-generation platinum compound, oxaliplatin (OX) exerts its anti-tumor effect by disrupting DNA synthesis and is even effective in cells resistant to cisplatin and carboplatin [ 5 ]. Moreover, OX also showed its anticancer function in BC chemotherapy [ 6 ]. Hence, to discover novel targets for treatment and improve the prognosis of BC patients, it is reasonable to explore the underlying mechanism of OX resistance in BC.…”