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miR-145 sensitizes gallbladder cancer to cisplatin by regulating multidrug resistance associated protein 1

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Tumor Biology

Abstract

Gallbladder cancer (GBC) is the most common malignancy in biliary tract with poor prognosis. Due to its high chemoresistance, systemic chemotherapies have had limited success in treating GBC patients. MicroRNAs (miRNAs) are emerging novel regulators of chemoresistance, which modulate the expression of drug resistance-related genes. In this study, we investigated the association between miR-145 expression and cisplatin sensitivity by both in vivo and in vitro analysis. Quantitative PCR (q-PCR) analysis indicated an increased miR-145 expression in GBC tissues. In addition, studies on GBC cell lines suggested an increased cisplatin efficacy with miR-145 overexpression, whereas decreasing miR-145 expression reduced cisplatin sensitivity. Further, we found that miR-145 accelerated MRP1 mRNA degradation by directly targeting its 3′-UTR and therefore caused increased cisplatin toxicity in GBC cells. Moreover, lower miR-145 and higher MRP1 expression levels predicted poor prognosis in GBC patients who received chemotherapy. Collectively, our findings established a rationale for using miR-145 expression as a biomarker to identify cisplatin-resistant GBC patients and propose that treatment strategies increasing the expression of miR-145 could be a new therapeutic approach for GBC patients.

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Acknowledgments

This work was supported by the National Science Foundation of China (81072011, 81272748, and 81472240), National Key Technology R&D Program (2012BAI06B01), Foundation of Science and Technology Commission of Shanghai Municipality (12XD1403400), and Foundation of Shanghai Municipal Health Bureau (XBR2011035).

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    1. Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China

      Ming Zhan, Xiaonan Zhao, Hui Wang, Wei Chen, Sunwang Xu, Wei Wang, Hui Shen, Shuai Huang & Jian Wang

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    1. Ming Zhan
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    2. Xiaonan Zhao
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    Correspondence to Jian Wang.

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    Ming Zhan and Xiaonan Zhao contributed equally to this work.

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    Zhan, M., Zhao, X., Wang, H. et al. miR-145 sensitizes gallbladder cancer to cisplatin by regulating multidrug resistance associated protein 1. Tumor Biol. 37, 10553–10562 (2016). https://doi.org/10.1007/s13277-016-4957-6

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