Fu Hui, Fu Lei, Xie Chao, Zuo Wen-Shu, Liu Yan-Song, Zheng Mei-Zhu, Yu Jin-Ming
Department of Breast Disease Centre, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong 250117, P.R. China.
Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong 250117, P.R. China.
Oncol Rep. 2017 Feb;37(2):1093-1099. doi: 10.3892/or.2017.5360. Epub 2017 Jan 9.
Cancer stem cell (CSC) formation and epithelial-mesenchymal transition (EMT) are pivotal events in tumor cell invasion and metastasis. They have been shown to occur in resistance to tamoxifen. Moreover, microRNAs (miRNAs) have been associated with CSCs, EMT as well as tamoxifen resistance. Studying molecular mechanism of CSCs, EMT as well as tamoxifen resistance will help us to further understand the pathogenesis and progression of the disease and offer new targets for effective therapies. In the present study, we showed that miR-375 inhibits CSC traits in breast cancer MCF-7 cells. Bioinformatics analysis and experimental validation identified HOXB3 as a direct target of miR-375. Overexpressing miR-375 degraded HOXB3 mRNA in MCF-7 cells. Moreover, overexpression of HOXB3 induced formation of CSC phenotypes, EMT and tamoxifen-resistance as well as enhanced ability of migration and invasion in MCF-7 cells. Most ER-positive breast cancer-related deaths occur, because of resistance to standard therapies and metastasis, restoring miR-375 or targeting HOXB3 might serve as potential therapeutic approaches for the treatment of tamoxifen-resistant breast cancer.
癌症干细胞（CSC）的形成和上皮-间质转化（EMT）是肿瘤细胞侵袭和转移的关键事件。已证明它们在对他莫昔芬的耐药性中会发生。此外，微小RNA（miRNA）与癌症干细胞、上皮-间质转化以及他莫昔芬耐药性有关。研究癌症干细胞、上皮-间质转化以及他莫昔芬耐药性的分子机制将有助于我们进一步了解该疾病的发病机制和进展，并为有效治疗提供新的靶点。在本研究中，我们表明miR-375抑制乳腺癌MCF-7细胞中的癌症干细胞特性。生物信息学分析和实验验证确定HOXB3是miR-375的直接靶点。过表达miR-375会降解MCF-7细胞中的HOXB3 mRNA。此外，HOXB3的过表达诱导了MCF-7细胞中癌症干细胞表型的形成、上皮-间质转化和他莫昔芬耐药性，以及增强了迁移和侵袭能力。大多数雌激素受体阳性乳腺癌相关死亡是由于对标准疗法的耐药性和转移，恢复miR-375或靶向HOXB3可能作为治疗他莫昔芬耐药性乳腺癌的潜在治疗方法。
