Resistance to cancer chemotherapeutic drugs is determined by pivotal microRNA regulators

Chemo-resistance, which is the main obstacle in cancer therapy, is caused by the onset of drug-resistant cells in the heterogeneous cell population in cancer tissues. MicroRNAs regulate gene expression at the post-transcriptional level, and they are involved in many different biological processes, including cell proliferation, differentiation, metabolism, stress response, and apoptosis. The aberrant expression of microRNAs plays a major pathogenic role from the early stages of the carcinogenesis process. Recently, microRNAs have been reported to play an important role in inducing resistance to anti-cancer drugs. Specific microRNA alterations occur selectively in cancer cells, rendering these cells resistant to various chemotherapeutic agents. For example, resistance to 5-fluorouracil is mediated by alterations in miR-21, miR-27a/b, and miR-155; the sensitivity to Docetaxel is influenced by miR-98, miR-192, miR-194, miR-200b, miR-212, and miR-424; and the resistance to Cisplatin is mediated by miR-let-7, miR-15, miR-16 miR-21 and miR-214. Chemo-resistant cancer cells are characterized by altered functions in enzymes that are involved in microRNA maturation, primarily including Dicer, as demonstrated in ovarian cancer, oral squamous cell carcinoma, breast cancer and cervical cancer. Based on the evidence reviewed in this paper, various strategies have been developed to artificially re-establish microRNA expression in resistant cells, thus restoring chemo-sensitivity. These strategies employ synthetic analogs, anti-microRNA oligonucleotides, locked nucleic acid, microRNA sponges, drugs that inhibit DNA methylation or histone deacetylation, and the introduction of microRNA mimics. The ability to modulate microRNA expression is a promising strategy for overcoming the problem of drug resistance in cancer treatment.