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MicroRNAs: master regulators of drug resistance, stemness, and metastasis

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Abstract

MicroRNAs (miRNAs) are 20–22 nucleotides long small non-coding RNAs that regulate gene expression post-transcriptionally. Last decade has witnessed emerging evidences of active roles of miRNAs in tumor development, progression, metastasis, and drug resistance. Many factors contribute to their dysregulation in cancer, such as chromosomal aberrations, differential methylation of their own or host genes’ promoters and alterations in miRNA biogenesis pathways. miRNAs have been shown to act as tumor suppressors or oncogenes depending on the targets they regulate and the tissue where they are expressed. Because miRNAs can regulate dozens of genes simultaneously and they can function as tumor suppressors or oncogenes, they have been proposed as promising targets for cancer therapy. In this review, we focus on the role of miRNAs in driving drug resistance and metastasis which are associated with stem cell properties of cancer cells. Furthermore, we discuss systems biology approaches to combine experimental and computational methods to study effects of miRNAs on gene or protein networks regulating these processes. Finally, we describe methods to target oncogenic or replace tumor suppressor miRNAs and current delivery strategies to sensitize refractory cells and to prevent metastasis. A holistic understanding of miRNAs’ functions in drug resistance and metastasis, which are major causes of cancer-related deaths, and the development of novel strategies to target them efficiently will pave the way towards better translation of miRNAs into clinics and management of cancer therapy.

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Acknowledgments

We thank Gülce Itır Perçin, Merve Bal, Mustafa Can Kiren and Ezgi Bağırsakçıoğlu for helping us prepare the figures and tables. We thank Dr. Martin Ebeling for insights and discussions on network-based analysis. We apologize to the many authors whose work could not be cited directly because of space limitations. This work was supported by EMBO Installation Grant (ÖŞ), Bilkent University start-up funds (ÖŞ) and the scholarship from Higher Education Commission of Pakistan (UR).

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  1. Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey

    Umar Raza & Özgür Şahin

  2. Bioinformatics and Exploratory Data Analysis, Pharmaceutical Research and Early Development (pRED), F. Hoffmann-La Roche AG, 4070, Basel, Switzerland

    Jitao David Zhang

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  1. Umar Raza
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Raza, U., Zhang, J.D. & Şahin, Ö. MicroRNAs: master regulators of drug resistance, stemness, and metastasis. J Mol Med 92, 321–336 (2014). https://doi.org/10.1007/s00109-014-1129-2

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