Chen Danni, Bao Chang, Zhao Feng, Yu Haogang, Zhong Guansheng, Xu Liang, Yan Senxiang
Department of Radiation Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Front Oncol. 2020 Aug 21;10:1397. doi: 10.3389/fonc.2020.01397. eCollection 2020.
Breast cancer is the most prevalent type of malignancy in women worldwide. Taxanes (paclitaxel and docetaxel) are widely applied as first-line chemotherapeutic agents, while the therapeutic effect is seriously limited by the development of drug resistance. In the present study, we screened out several miRNAs dysregulated in taxanes-resistant breast cancer samples and confirmed that two miRNAs (miR-335-5p and let-7c-5p) played a major role in cell proliferation, apoptosis, and chemo-resistance. In addition, the weighted gene co-expression network analysis (WGCNA) for potential target genes of miR-335-5p and let-7c-5p identified three hub genes (CXCL9, CCR7, and SOCS1) with a positive relationship to taxanes-sensitivity. Further, target relationships between miR-335-5p and CXCL9, let-7c-5p and CCR7/SOCS1 were confirmed by dual-luciferase reporter assays. Importantly, the regulatory functions of CXCL9, CCR7, and SOCS1 on proliferation and chemoresistance were validated. In conclusion, our study shed light on clinical theragnostic relationships between miR-335-5p/CXCL9, let-7c-5p/CCR7/SOCS1 axes, and taxanes-resistance in breast cancer.
乳腺癌是全球女性中最常见的恶性肿瘤类型。紫杉烷类(紫杉醇和多西他赛)作为一线化疗药物被广泛应用,但其治疗效果受到耐药性发展的严重限制。在本研究中,我们筛选出了几种在紫杉烷耐药乳腺癌样本中表达失调的miRNA,并证实了两种miRNA(miR-335-5p和let-7c-5p)在细胞增殖、凋亡和化疗耐药中起主要作用。此外,对miR-335-5p和let-7c-5p的潜在靶基因进行加权基因共表达网络分析(WGCNA),确定了三个与紫杉烷敏感性呈正相关的枢纽基因(CXCL9、CCR7和SOCS1)。进一步通过双荧光素酶报告基因检测证实了miR-335-5p与CXCL9、let-7c-5p与CCR7/SOCS1之间的靶向关系。重要的是,验证了CXCL9、CCR7和SOCS1对增殖和化疗耐药的调节功能。总之,我们揭示了miR-335-5p/CXCL9、let-7c-5p/CCR7/SOCS1轴与乳腺癌紫杉烷耐药之间的临床诊疗关系。