奥沙利铂是继顺铂、卡铂之后的第三代铂类化疗药，有效性和安全性高于前两代铂类，被广泛用于结直肠癌、胃癌、肝癌、胰腺癌等恶性肿瘤，可抑制癌细胞染色体脱氧核糖核酸（DNA）复制和转录。不过，奥沙利铂对乳腺癌的疗效不如顺铂和卡铂。既往研究发现，由于致癌激活和DNA复制应激，细胞有丝分裂周期检查点激酶CHK1高表达于大多数癌细胞。因此，CHK1失活可引起基因组不稳定、染色体突变和癌细胞死亡，是一种有希望的癌症疗法。
2020年10月11日，英国《自然》旗下《肿瘤形成》在线发表韩国淑明女子大学、延世大学、首尔大学的研究报告，发现抑制CHK1活性可显著增强奥沙利铂对三阴性乳腺癌的疗效。
该研究首选对三阴性乳腺癌组织与邻近正常组织由DNA转录而来的29种小分子核糖核酸（miRNA）进行比较，其中miR-320c显著低表达，而且其靶蛋白为CHK1。此外，miR-320c低表达与高表达的三阴性乳腺癌患者相比，总生存比例显著较低。由于CHK1与DNA损伤修复密切相关，故该研究采用顺铂、卡铂、奥沙利铂诱发DNA损伤，进一步分析miR-320c对三阴性乳腺癌细胞DNA损伤修复的影响，结果表明奥沙利铂＋miR-320c对DNA损伤修复的抑制作用最强。
体外细胞分析表明，提高三阴性乳腺癌的miR-320c表达水平，可抑制CHK1的DNA损伤修复作用，从而提高奥沙利铂的疗效。
最后，将人类三阴性乳腺癌细胞注入小鼠体内建立肿瘤异种移植模型，随后给予miR-320c类似物＋奥沙利铂可有效抑制肿瘤生长。
因此，该研究结果表明，miR-320c通过抑制CHK1可显著增强奥沙利铂对三阴性乳腺癌的疗效，可能成为奥沙利铂疗效的预测指标，也有望成为增强三阴性乳腺癌化疗效果的靶向分子，故有必要进一步开展临床研究进行验证。
Oncogenesis. 2020 Oct 11. Online ahead of print.
Inhibition of Chk1 by miR-320c increases oxaliplatin responsiveness in triple-negative breast cancer.
Sera Lim, Yesol Kim, Soo-Been Lee, Hyeok-Gu Kang, Da-Hyun Kim, Jee Won Park, Daeun Chung, Hyunkyung Kong, Kyung Hyun Yoo, Yonghwan Kim, Wonshik Han, Kyung-Hee Chun, Jong Hoon Park.
Sookmyung Women's University, Seoul, Korea; Yonsei University College of Medicine, Seoul, Korea; Seoul National University College of Medicine, Seoul, Korea.
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.
DOI: 10.1038/s41389-020-00275-x
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