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5-Fluorouracil is a classic chemotherapeutic drug that is widely used to treat various cancers. However, patients often exhibit primary or acquired drug resistance during treatment with 5-fluorouracil chemotherapy. 5-Fluorouracil resistance is a multifactorial event that involves abnormal enzyme metabolism, transport deregulation, cell cycle disorders, apoptosis resistance, and mismatch repair deficiency. Despite advancements in bioresearch technologies in the past several decades, the molecular mechanisms of 5-fluorouracil resistance have not been completely clarified. Recently, microarray analyses have shown that noncoding RNAs (i.e. microRNAs and long noncoding RNAs) play a vital role in 5-fluorouracil resistance in multiple cancer cell lines. These noncoding RNAs can function as oncogenes or tumor suppressors, contributing to 5-fluorouracil drug resistance. In this review, we discuss the effects of microRNAs on 5-fluorouracil sensitivity via targeting of metabolic enzymes, the cell cycle, apoptosis, autophagy, the epithelial–mesenchymal transition, and cancer stem cells. In particular, we focus on summarizing current knowledge on the molecular mechanisms through which long noncoding RNAs mediate 5-fluorouracil drug resistance. Moreover, we describe the specific microRNAs that may function as markers for prediction of chemotherapeutic response to 5-fluorouracil. This review will help to improve the current understanding of how to reverse 5-fluorouracil resistance and may facilitate the establishment of new strategies for alleviating drug resistance in the future.

Insights into the involvement of noncoding RNAs in 5-fluorouracil drug resistance