Involvement of miR-451 in resistance to paclitaxel by regulating YWHAZ in breast cancer

• Published in: Cell death & disease Vol. 8; no. 10; p. e3071
• Main Authors: Wang, Wenrui, Zhang, Lingyu, Wang, Yangyang, Ding, Yongxing, Chen, Tiantian, Wang, Yueyue, Wang, Haifeng, Li, Yu, Duan, Kecai, Chen, Sulian, Yang, Qingling, Chen, Changjie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.10.2017; Springer Nature B.V; Nature Publishing Group
• Subjects: 14-3-3 Proteins - genetics; 631/337/384/331; 631/67/1059/2326; 631/67/1059/602; 692/699/67/1347; Animals; Antibodies; Apoptosis; Apoptosis - genetics; Biochemistry; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; c-Myc protein; Cell adhesion & migration; Cell Biology; Cell Culture; Cell migration; Cell Movement - genetics; Cell Proliferation - genetics; Cyclin D1; Drug resistance; Drug Resistance, Neoplasm - genetics; Ectopic expression; Female; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Immunology; Life Sciences; MCF-7 Cells; Mice; MicroRNAs - genetics; miRNA; Molecular modelling; Monooxygenase; Myc protein; Original; original-article; Paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - adverse effects; Post-transcription; siRNA; Transcription; Tumor cell lines; Xenograft Model Antitumor Assays; Xenografts; β-Catenin
• DOI: 10.1038/cddis.2017.460
• ISSN: 2041-4889

MicroRNAs (miRNAs) have been identified as major post-transcriptional regulators of the initiation and progression of human cancers, including breast cancer. However, the detail role of miR-451 has not been fully elucidated in breast cancer. In this study, we aimed to investigate the biological role and molecular mechanisms of miR-451 in drug resistance in breast cancer cell lines and in xenograft model. We show that miR-451 is decreased in human breast cancer specimens and in paclitaxel-resistant (PR) cells. Ectopic expression of miR-451 could inhibit the cell migration and invasion, promoted apoptosis, induced cell-cycle arrest Furthermore, tyrosine3-monooxygenase/tryptophan5-monooxygenase activation protein zeta (YWHAZ) was identified as a direct target of miR-451. Remarkably, the expression of YWHAZ is inversely correlated with the level of miR-451 in human breast cancer samples. Co-treatment with miR-451 mimics and YWHAZ-siRNA significantly enhanced YWHAZ knockdown in both SKBR3/PR and MCF-7/PR cells Moreover, miR-451 markedly inhibited expression of β -catenin via YWHAZ and subsequently inhibited downstream gene cyclin D1, c-Myc expression. The results of xenograft model in vivo showed that intratumor injection of miR-451 agomir induced a tumor-suppressive effect in SKBR3/PR drug-resistant xenograft model. Taken together, our findings suggested that miR-451 might be considered as important and potential target in paclitaxel-resistant breast cancer treatment.