Background

Cancer is a serious threat to human life and health, and in recent years, it has become a leading cause of death in humans. According to statistical reports, new cases of cancer reached 14.1 million worldwide, and the total number of cancer-related deaths reached 8.2 million in 2012. With an increase in life expectancy and deterioration of the global ecosystem, the incidence of cancer is increasing. It is expected that the number of new cases will reach 23.6 million by 2030 [1].

Currently, chemotherapy, radiotherapy, and surgery are the most common cancer therapies. For cancers such as lymphoma, leukemia, small cell lung cancer, chemotherapy is the first line of treatment. For other solid tumors, chemotherapy can be used as an auxiliary treatment to eliminate postoperative residual nodules to prevent relapse or as pre-local tumor before surgery or radiotherapy. In addition, chemotherapy is also used as palliative care in patients who cannot undergo radical surgery [2]. In recent decades, chemotherapy drugs have made great progress, but the occurrence of tumor drug resistance often leads to treatment failure. For advanced cancer patients, drug-resistance is a major obstacle to successful treatment [3]. According to statistical reports, more than 90% of deaths of tumor patients are associated with chemotherapeutic drug resistance [4, 5]. Overall, drug resistance can be divided into endogenous and acquired drug resistance, and the underlying mechanisms need to be elucidated. At present, it is believed that the increase in drug efflux, target switch, cell cycle checkpoints alteration, apoptosis inhibition, and increase in DNA damage repair are all related to drug resistance [6].

MiRNAs are small non-coding RNAs with a length of approximately 19–25 nt, which can regulate various target genes. MiRNAs are involved in the regulation of a variety of biological processes, such as cell cycle, differentiation, proliferation, apoptosis, stress tolerance, energy metabolism, and immune response [7]. The biogenesis of miRNAs in animal cells and the mechanisms of regulation of their target gene expression are shown in Fig. 1. In simple terms, this process can be divided into the following steps [8, 9]: (1) the miRNA gene is transcribed into primary miRNA (pri-miRNA) by RNA polymeraseII(RNA polII) in the nucleus; (2) pri-miRNA is processed by the Drosha/DGCR8 complex to release the intermediate precursor miRNA (pre-miRNA), which is approximately 70 nt with a stem loop structure and a 2 nt overhang at the 3′-end; (3) pre-miRNA binds to the Exp5/Ran-GTP complex, which allows for its transport into the cytoplasm; (4) the pre-miRNA is then processed into double-stranded RNA by the Dicer/TRBP/PACT complex in the cytoplasm; (5) the miRNA-duplex is unwound into single strands by the action of helicase. Under normal circumstances, the RNA strand with lower stability at the 5′-end will be integrated into the RNA-induced silencing complex (RISC) and become a mature miRNA, and the strand with higher stability at the 5′-end will be degraded; (6) miRNA-induced silencing complex (miRISC) will bind to the 3′-untranslated regions (UTR) of the target mRNA, thus inhibiting its translation.

Fig. 1
figure 1

The mechanisms of microRNA biogenesis and its regulation of gene expression. The solid arrows represents the classical pathway, the dotted arrows represents the non-classical pathway

Full size image

In plant cells, miRISC will degrade its target mRNA, and the biogenesis of miRNAs is slightly different from that in animal cells [10].

Existing research shows that this classical processing and functioning pathway has some exceptions. For example, in step (2) of its biosynthesis process, the pri-miRNA can also be processed into pre-miRNA in a Drosha-independent way [11]. In step (5), the two strands may be randomly integrated into RISC, or they could bind to mRNA in RISC-independent manner [183]. In recent years, a large number of studies have found that miRNAs could directly target drug efflux pump, thereby regulating cell resistance to drugs. For example, in HCC, miRNA-223 targeted ABCB1, thereby downregulating the cell resistance to DOX [51]. MiRNA-133a targeted ABCC1, rendering the cells more sensitive to ADM [52]. MiRNA-298 was found to target ABCC1 in breast cancer cells, increasing sensitivity of cells to DOX [184]. MiRNA-328 and miRNA-487a could enhance cell sensitivity to mitoxantrone (MX) by targeting ABCG2 in breast cancer [185, 186]. Other ABC-related genes, such as ABCA1 and ABCB9, were regulated by miRNA-31 and miRNA-106a, and they regulated drug resistance of lung cancer cells to CDDP [58, 63]. Let-7c targeted ABCC2 in NSCLC, increasing sensitivity to gefitinib [57].

Some chemotherapeutic agents such as CDDP and DOX induce cell apoptosis via DNA damage. Damaged DNA strands require DNA damage repair enzymes to repair the affected sequences. Once the damage DNA chains were repaired, the cell can continue to survive. There are a lot of enzymes involved in the repair of DNA damage, and changes in their expression influence drug resistance to DNA damaging agents. Some miRNAs reverse drug resistance by targeting DNA damage repair-related enzyme genes. For example, miRNA-9 targeted BRCA1 in ovarian cancer, thereby increasing sensitivity of cells to CDDP [83]. MiRNA-138 targeted ERCC1 in NSCLC, thus increasing sensitivity to CDDP [59]. Obviously, inhibition of DNA damage repair systems to increase the efficacy of DNA damage agents is a promising approach in the treatment of cancer.

Conclusions

The discovery of miRNAs has deepened our understanding of human diseases, including cancer. In this article, we have reviewed miRNAs that regulate resistance to chemotherapy in different tumors. The expression of miRNAs is regulated by a series of factors and dysregulated miRNA expression often leads to antitumor drug resistance. The interaction of miRNAs with mRNA, protein, and other non-encoding RNA constitutes their whole regulatory network. The complexity of this network gives miRNAs a wide range of biological functions, which, at the same time, ensure its great potential for clinical application. For example, the “inhibition” or the “replacement” treatment strategy can be performed based on the upregulation or downregulation of miRNAs in cancer cells, respectively [187]. In addition, the expression of miRNAs has been validated as prognosis indicators in patients with certain cancers. Last but not least, miRNAs could act as promising clinical cancer biomarkers [188]. However, there is still a long way before complete clinical applications of miRNAs are fully developed.

As mentioned above, miRNAs are considered to have great potential in the treatment of cancer. Indeed, the efficacy and safety of miRNA-related treatments are better than those of treatments based on siRNA [189]. Although the role of miRNA in reversing drug resistance is unquestionable, there are still several important issues that need to be further addressed. First, due to the heterogeneity of tumor cells and the diversity of anticancer drugs, some miRNAs have different regulatory effects on drug resistance in different types of tumors, some even being the opposite. Therefore, it is necessary to further and extensively confirm the mechanisms and effects of these miRNAs regulating cellular drug resistance and to screen some of the miRNAs with broad-spectrum regulation of resistance for mechanism research and clinical development. Second, in vitro studies are abundant, whereas in vivo studies are still relatively rare. Given the complexity of the animal’s internal environment, some miRNAs that exhibit good regulation of drug resistance in in vitro studies may not necessarily be effective in vivo. Therefore, the effects of most of the miRNAs need to be further verified in vivo. Third, miRNAs are large molecules; therefore, studies regarding their timely and effective targeting and entry into tumor cells in the body require attention. At present, there are very few studies in this field. Methods such as coupling specific tumor ligands onto the surface of the miRNA-based drugs ensure that miRNAs can be transported to tumor tissues to a greater extent, as well as reduce the side effects and improve the safety of miRNA drugs [190]. Fourth, the safety of miRNAs in vivo has yet to be evaluated systematically.

Taking into account that miRNAs can effectively regulate tumor cell resistance to chemotherapy, the use of miRNA in combination with chemotherapy to achieve a better therapeutic effect is promising. For example, Wu et al. [191] tried to combine miRNA-27b with a variety of anticancer drugs. They found that this miRNA could enhance the anticancer effect of chemotherapy by p53 activation and CYP1B1 inhibition, indicating that the miRNA and the drug had obvious synergistic effect in cancer treatment. In addition, some studies have attempted to encapsulate miRNAs with small molecule drugs in a nano-carrier. Some examples include the co-encapsulation of miRNA-205 and GEM in a nano-carrier for pancreatic cancer treatment [192], co-encapsulation of miRNA-34a, and DOX for breast cancer treatment [193]. These studies showed that the combined action of drug-resistance regulatory miRNAs and chemotherapy drugs had a synergistic effect on tumor cells inhibition, which could improve the effects of chemotherapy drugs, and reverse drug resistance to a certain extent. Based on the mechanisms of tumor cell resistance to chemotherapy, the combination of miRNAs with chemotherapy drugs will be a very promising therapeutic regimen for inhibiting or killing tumor cells in the future, which is worth further study.