强力霉素通过PAR-1/NF-κB/miR-17/上皮钙黏蛋白途径抑制乳腺癌上皮-间质转化和转移。

Doxycycline inhibits breast cancer EMT and metastasis through PAR-1/NF-κB/miR-17/E-cadherin pathway.

作者信息

Zhong Weilong, Chen Shuang, Qin Yuan, Zhang Heng, Wang Hongzhi, Meng Jing, Huai Longcong, Zhang Qiang, Yin Tingting, Lei Yueyang, Han Jingxia, He Lingfei, Sun Bo, Liu Huijuan, Liu Yanrong, Zhou Honggang, Sun Tao, Yang Cheng

机构信息

State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300000, China.

Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, 300000, China.

出版信息

Oncotarget. 2017 Aug 24;8(62):104855-104866. doi: 10.18632/oncotarget.20418. eCollection 2017 Dec 1.

Doxycycline displays high efficiency for cancer therapy. However, the molecular mechanism is poorly understood. In our previous study, doxycycline was found to suppress tumor progression by directly targeting proteinase-activated receptor 1 (PAR1). In this study, microRNAs were found to be involved in PAR1-mediated anti-tumor effects of doxycycline. Among these miRNAs, miR-17 was found to promote breast cancer cell metastasis both and . Moreover, miR-17 could reverse partial doxycycline inhibition effects on breast cancer. Employing luciferase and chromatin immunoprecipitation assays, nuclear factor-kappaB (NF-κB) was found to bind miR-17 promoters. Furthermore, E-cadherin was identified as the target gene of miR-17. These results showed that miR-17 can resist the inhibitory effects of doxycycline on breast cancer epithelial-mesenchymal transformation (EMT) by targeting E-cadherin.

强力霉素在癌症治疗中显示出高效性。然而，其分子机制尚不清楚。在我们之前的研究中，发现强力霉素通过直接靶向蛋白酶激活受体1（PAR1）来抑制肿瘤进展。在本研究中，发现微小RNA参与了强力霉素介导的抗肿瘤作用。在这些微小RNA中，发现miR-17在体内和体外均促进乳腺癌细胞转移。此外，miR-17可以逆转强力霉素对乳腺癌的部分抑制作用。采用荧光素酶和染色质免疫沉淀分析，发现核因子-κB（NF-κB）与miR-17启动子结合。此外，E-钙黏蛋白被鉴定为miR-17的靶基因。这些结果表明，miR-17可通过靶向E-钙黏蛋白抵抗强力霉素对乳腺癌上皮-间质转化（EMT）的抑制作用。