Research Papers:

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

Miao Chen, Daojiang Li, Ni Gong, Hao Wu, Chen Su, Canbin Xie, Hong Xiang, Changwei Lin and Xiaorong Li _

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Oncotarget. 2017; 8:52983-52994. https://doi.org/10.18632/oncotarget.17677

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Miao Chen1, Daojiang Li1, Ni Gong1, Hao Wu1, Chen Su1, Canbin Xie1, Hong Xiang2, Changwei Lin1 and Xiaorong Li1

1Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P. R. China

2Laboratory Medical Center, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P. R. China

Correspondence to:

Xiaorong Li, email: lixiaorong@medmail.com.cn

Changwei Lin, email: linchangwei1987@csu.edu.cn

Keywords: colorectal cancer, miR-133b, ABCC1, multidrug resistance, chemosensitivity

Received: December 28, 2016     Accepted: March 03, 2017     Published: May 08, 2017


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 in vivo 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 in vitro 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 in vivo inhibited tumor growth induced by CRC drug-resistant cells. A xenograft from the in vivo 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.

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