MicroRNA Regulation in Drug Resistance Mechanisms

MicroRNAs are small non-coding RNA molecules that fine-tune gene expression by binding to target messenger RNAs, often within their 3′-untranslated regions, to repress translation or promote degradation. In the context of drug resistance, aberrant microRNA expression can alter the levels of drug-metabolising enzymes, efflux transporters, apoptotic regulators and key signalling molecules. Such dysregulation contributes to reduced intracellular drug accumulation, evasion of cell death and activation of survival pathways. Moreover, microRNAs can orchestrate complex networks by targeting transcription factors and epigenetic modulators, thereby reinforcing resistant phenotypes across diverse cancer types. Understanding these regulatory circuits has global significance for improving therapeutic efficacy, guiding personalised treatment strategies and developing microRNA-based therapeutics to overcome resistance.

Research from Nature Portfolio

Recent studies have delineated a direct role for specific microRNAs in the post-transcriptional control of drug-metabolising enzymes. For example, one investigation demonstrated that hsa-miR-128-3p binds to the 3′-untranslated region of CYP2C9 transcripts in liver cells, leading to marked suppression of this key enzyme and revealing an inverse correlation between miR-128-3p levels and CYP2C9 expression in hepatocellular carcinoma specimens. In a separate advance, a bioengineered prodrug of pre-microRNA-34a was shown to release mature miR-34a in orthotopic osteosarcoma mouse models, inducing apoptosis, enforcing G2 cell-cycle arrest and robustly reducing tumour growth. These findings underscore both the pathogenic impact of microRNA dysregulation on drug metabolism and the therapeutic promise of microRNA replacement strategies.

MicroRNA Regulation in Drug Resistance Mechanisms publication trend

The graph below shows the total number of articles in microrna regulation in drug resistance mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

microRNA: A short non-coding RNA that regulates gene expression by binding target mRNAs, leading to translational repression or degradation.

3′-untranslated region (3′-UTR): The section of an mRNA downstream of the coding sequence that often contains binding sites for regulatory RNA and proteins.

ATP-binding cassette (ABC) transporter: A family of membrane proteins that utilise ATP hydrolysis to efflux diverse substrates, including drugs, from cells.

Apoptosis: Programmed cell death characterised by caspase activation, DNA fragmentation and membrane blebbing, essential for tissue homeostasis and response to therapy.

Epithelial–mesenchymal transition (EMT): A phenotype switch in which epithelial cells acquire mesenchymal traits, promoting invasion, metastasis and resistance to treatment.

Prodrug: A precursor compound that is metabolically or enzymatically converted in vivo into an active therapeutic agent.

References

1. Suppression of CYP2C9 by MicroRNA hsa-miR-128-3p in Human Liver Cells and Association with Hepatocellular Carcinoma. Scientific Reports (2015).
2. Genetically engineered pre-microRNA-34a prodrug suppresses orthotopic osteosarcoma xenograft tumor growth via the induction of apoptosis and cell cycle arrest. Scientific Reports (2016).
3. MicroRNA as a Potential Therapeutic Molecule in Cancer. Cells (2022).
4. Down-regulation of miR-210-3p encourages chemotherapy resistance of renal cell carcinoma via modulating ABCC1. Cell & Bioscience (2018).
5. Non-Coding RNAs and Resistance to Anticancer Drugs in Gastrointestinal Tumors. Frontiers in Oncology (2018).