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.

由于致癌激活和持续的复制压力，检查点激酶 1 (Chk1) 表达在大多数癌症中得到增强。Chk1 失活是一种很有前景的癌症治疗方法，因为它的失活会导致基因组不稳定、染色体灾难和癌细胞死亡。在此，我们观察到在三阴性乳腺癌 (TNBC) 患者中下调的 miR-320c 可以靶向 Chk1。此外，下调的 miR-320c 表达与 TNBC 患者的总体生存率较差有关。由于 Chk1 与 DNA 损伤反应 (DDR) 相关，我们研究了 miR-320c 对 TNBC 细胞中 DDR 的影响。为了诱导 DNA 损伤，我们使用了铂类药物，尤其是奥沙利铂，它对 miR-320c 最有效。我们观察到 TNBC 中 miR-320c 的过表达通过体外 Chk1 的负调节介导 DNA 损伤修复来调节奥沙利铂反应性。此外，使用异种移植模型，miR-320c 模拟物和奥沙利铂的组合可有效抑制肿瘤进展。这些研究表明 miR-320c 作为奥沙利铂反应性的标志物和提高 TNBC 化疗疗效的治疗靶标的潜力。