miR-27b synergizes with anticancer drugs via p53 activation and CYP1B1 suppression

• Published in: Cell research 2015-04, Vol.25 (4), p.477-495
• Main Authors: Mu, Wenjing, Hu, Chaobo, Zhang, Haibin, Qu, Zengqiang, Cen, Jin, Qiu, Zhixin, Li, Chao, Ren, Haozhen, Li, Yixue, He, Xianghuo, Shi, Xiaolei, Hui, Lijian
• Format: Article
• Language: English
• Subjects: 631/337/384/331; 631/67/1504/1610; 631/67/589/1588; 692/700/565/1436; Animals; Antineoplastic Agents - administration & dosage; Apoptosis - genetics; Biomedical and Life Sciences; Cell Biology; Chemotherapy; Cytochrome P-450 CYP1B1 - genetics; Detoxification; Drug resistance; Drug Resistance, Neoplasm - genetics; Hep G2 Cells; Heterogeneity; Humans; Inactivation, Metabolic - genetics; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Kidneys; Life Sciences; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Niacinamide - administration & dosage; Niacinamide - analogs & derivatives; Original; original-article; Phenylurea Compounds - administration & dosage; RNA, Messenger - genetics; Tumor Suppressor Protein p53 - genetics; Xenograft Model Antitumor Assays
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2015.23

Liver and kidney cancers are notorious for drug resistance. Due to the complexity, redundancy and interpatient heterogeneity of resistance mechanisms, most efforts targeting a single pathway were unsuccessful. Novel personalized therapies targeting multiple essential drug resistance pathways in parallel hold a promise for future cancer treatment. Exploiting the multitarget characteristic of microRNAs (miRNAs), we developed a new therapeutic strategy by the combinational use of miRNA and anticancer drugs to increase drug response. By a systems approach, we identified that miR-27b, a miRNA deleted in liver and kidney cancers, sensitizes cancer cells to a broad spectrum of anticancer drugs in vitro and in vivo . Functionally, miR-27b enhances drug response by activating p53-dependent apoptosis and reducing CYP1B1-mediated drug detoxification. Notably, miR-27b promotes drug response specifically in patients carrying p53 -wild-type or CYP1B1-high signature. Together, we propose that miR-27b synergizes with anticancer drugs in a defined subgroup of liver and kidney cancer patients.