miR-133b down-regulates ABCC1 and enhances the sensitivity of CRC to anti-tumor drugs

• Published in: Oncotarget Vol. 8; no. 32; pp. 52983 - 52994
• Main Authors: Chen, Miao, Li, Daojiang, Gong, Ni, Wu, Hao, Su, Chen, Xie, Canbin, Xiang, Hong, Lin, Changwei, Li, Xiaorong
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 08.08.2017
• Subjects: Research Paper; multidrug resistance; ABCC1; colorectal cancer; miR-133b; chemosensitivity
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.17677

Multidrug resistance (MDR) is the main cause of failed chemotherapy treatments. Therefore, preventing MDR is pivotal in treating colorectal cancer (CRC). In a previous study miR-133b was shown to be a tumor suppressor. Additionally, in CRC cells transfected with miR-133b, ATP-binding cassette (ABC) subfamily C member 1(ABCC1) was shown to be significantly down regulated. Whether miR-133b also enhances the chemosensitivity of drugs used to treat CRC by targeting ABCC1 is still unclear. Here, we utilized flow cytometry and high-performance liquid chromatography (HPLC) analysis to identify the ability of miR-133b to reserve MDR in CRC. We then used a dual-luciferase reporter assay to validate that miR-133b targets ABCC1. Further experiments were designed to validate the method in which miR-133b reversed MDR in CRC cells. The results demonstrated that the level of miR-133b was down-regulated and the expression of ABCC1 was up-regulated in drug-resistant CRC cells compared to non-drug-resistant CRC cells. The restoration of miR-133b expression in CRC drug-resistant cells resulted in reduced IC50s to chemotherapeutic drugs, significantly induced G1 accumulation, inhibited growth and promoted necrosis in combination with either 5-fluorouracil (5-FU) or vincristine (VCR), and decreased the expression of ABCC1. The dual-luciferase assay demonstrated that miR-133b directly targets ABCC1. The combination of agomiRNA-133b with chemotherapeutic drugs inhibited tumor growth induced by CRC drug-resistant cells. A xenograft from the model resulted in up-regulated levels of miR-133b and down-regulated levels of ABCC1. Therefore, miR-133b enhances the chemosensitivity of CRC cells to anti-tumor drugs by directly down-regulating ABCC1. This discovery provides a therapeutic strategy in which miR-133b is used as a potential sensitizer for drug-resistant CRC.