MicroRNAs in pancreatic cancer drug resistance: mechanisms and therapeutic potential

Abstract

Pancreatic cancer (PC) remains one of the most lethal malignancies, primarily due to its intrinsic resistance to conventional therapies. MicroRNAs (miRNAs), key regulators of gene expression, have been identified as crucial modulators of drug resistance mechanisms in this cancer type. This review synthesizes recent advancements in our understanding of how miRNAs influence treatment efficacy in PC. We have thoroughly summarized and discussed the complex role of miRNA in mediating drug resistance in PC treatment. By highlighting specific miRNAs that are implicated in drug resistance pathways, we provide insights into their functional mechanisms and interactions with key molecular targets. We also explore the potential of miRNA-based strategies as novel therapeutic approaches and diagnostic tools to overcome resistance and improve patient outcomes. Despite promising developments, challenges such as specificity, stability, and effective delivery of miRNA-based therapeutics remain. This review aims to offer a critical perspective on current research and propose future directions for leveraging miRNA-based interventions in the fight against PC.

Keywords: chemoresistance mechanisms; drug resistance; microRNA; pancreatic cancer; therapeutic targeting.

FIGURE 1

The Biogenesis of miRNAs. In the canonical pathway, miRNA biogenesis begins in the nucleus where pri-miRNAs are transcribed by RNA polymerase II. The pri-miRNAs are then cleaved by the Drosha-DGCR8 complex to form precursor pre-miRNAs, which are exported to the cytoplasm via Exportin-1, Exportin-5, and others. In the cytoplasm, the pre-miRNAs are further processed by Dicer into mature miRNA duplexes. One strand of the duplex, the guide strand, is incorporated into the RISC, where it guides the complex to target mRNAs for silencing or degradation, ultimately regulating gene expression. In the non-canonical pathway, the generation of pri-miRNA is similar to the canonical pathway, but the processing of pri-miRNA into pre-miRNA does not fully depend on Drosha. In the non-canonical pathway, Dicer may directly process incompletely cleaved pri-miRNA or generate pre-miRNA through other enzyme systems, such as Argonaute proteins. In some cases, miRNAs from the non-canonical pathway may be directly cleaved and processed by mediators like Ago2 (a form of Argonaute protein). The mature miRNAs generated through the non-canonical pathway typically enter the RISC in the cytoplasm and participate in gene expression regulation. They may inhibit the translation of target genes or promote their degradation by binding to the 3′UTR of target mRNA.

FIGURE 2

Mechanisms by Which miRNAs Influence Tumor Treatment Resistance. (A) miRNAs regulate drug efflux pumps or transport proteins, affecting drug uptake and efflux in cancer cells. This modulation alters intracellular drug accumulation, contributing to treatment resistance. (B) miRNAs modulate key genes in apoptotic pathways, thereby influencing the sensitivity of tumor cells to drug-induced cell death. Changes in apoptosis regulation can lead to resistance against chemotherapy. (C) miRNAs regulate autophagy-related genes, impacting cellular responses to therapy. Enhanced autophagy is often associated with drug resistance in tumor cells. (D) miRNAs influence DNA repair pathways by targeting critical factors involved in DNA damage response. This modulation alters the effectiveness of DNA-damaging agents, contributing to therapy resistance.