Role of MicroRNAs in anti-cancer drug resistance
MicroRNAs (miRNAs) are key regulators of various cellular and developmental processes, and are closely linked to the pathogenesis of a number of diseases including cancer. In recent years, several miRNAs have been identified that are capable of modulating sensitivity/resistance to conventional or targeted anti-cancer drugs. These miRNAs may function in the development and maintenance of drug resistance as it appears in the clinic. This chapter introduces the phenomenon of (multi)drug resistance occurring in cancer cells and its underlying causes. Further, it outlines the role of miRNAs in biology and cancer, and describes anti-cancer drugs that affect miRNA expression. MiRNAs associated with drug resistance are listed, some miRNAs are experimentally shown to regulate drug sensitivity. These miRNAs operate by repressing the expression of novel and known resistance-related genes and/or signaling pathways. However, the relevant target genes are often not known. Special attention is given to miR-519c involved in regulating ABCG2, and to miR-21 and miR-214 that both target PTEN thereby regulating the PI3K/Akt pathway. MiR-221 and miR-222 are described, they play a role in tumor necrosis factor related apoptosis inducing ligand (TRAIL) and tamoxifen resistance through the repression of multiple genes including p27 Kip1 . Similarly, the miR-200 family, essential for the regulation of epithelial-mesenchymal transition associated with cancer progression and drug resistance, is reviewed. Finally, the possibilities for diagnostic and therapeutic applications of miRNAs and how they may help to overcome drug resistance by re-sensitizing resistant cancer cells are discussed.