MicroRNA-Mediated Drug Resistance in Colorectal Cancer

Colorectal cancer remains a leading cause of cancer-related mortality worldwide, with chemotherapeutic regimens centred on agents such as 5-fluorouracil and oxaliplatin. A major obstacle to effective treatment is the development of drug resistance, frequently underpinned by dysregulation of microRNAs (miRNAs). These small non-coding RNAs fine-tune gene expression by targeting messenger RNAs and thereby modulate key cellular processes including apoptosis, autophagy and epithelial–mesenchymal transition. Altered miRNA expression may occur within tumour cells or in circulating compartments, often packaged in exosomes, and can serve both as mediators of resistance and as predictive biomarkers. Mechanistic studies have revealed that specific miRNAs interact with signalling networks—for example, by suppressing pro-apoptotic factors or enhancing survival pathways—to blunt the cytotoxic effects of chemotherapy. Insights into miRNA-driven resistance pathways hold promise for personalised approaches to overcome treatment failure and improve patient outcomes.

Research from Nature Portfolio

Recent studies have demonstrated dynamic regulation of circulating miRNAs during 5-fluorouracil-based therapy. Levels of several miRNAs decline during early treatment but rebound at later time points in responders, indicating their prognostic potential in predicting disease recurrence and progression. This temporal pattern suggests that monitoring peripheral miRNA expression could refine risk stratification and guide treatment adjustments. Complementary mechanistic work has elucidated how miR-625-3p drives resistance to oxaliplatin by directly targeting the MAP2K6–p38 mitogen-activated protein kinase axis. Suppression of this signalling cascade abrogates apoptosis and cell-cycle control, thereby promoting survival of resistant cells. Restoration of MAP2K6 activity or inhibition of miR-625-3p re-sensitises cells to oxaliplatin, highlighting a conceivable therapeutic intervention to reverse drug resistance.

MicroRNA-Mediated Drug Resistance in Colorectal Cancer publication trend

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

Technical terms

MicroRNA (miRNA): A class of short non-coding RNA molecules that regulate gene expression post-transcriptionally by binding to target messenger RNAs.

Exosome: A small extracellular vesicle released by cells, containing proteins, lipids and nucleic acids, including miRNAs, which facilitate intercellular communication.

Apoptosis: A programme of controlled cell death essential for maintaining tissue homeostasis and eliminating damaged or malignant cells.

Epithelial–mesenchymal transition (EMT): A biological process whereby epithelial cells acquire mesenchymal traits, increasing motility, invasiveness and resistance to therapy.

Autophagy: A cellular degradation pathway that recycles intracellular components, which can promote survival of cancer cells under therapeutic stress.

Chemoresistance: The ability of cancer cells to withstand and survive cytotoxic drug treatment, often leading to therapeutic failure and disease progression.

References

1. Baseline Expression of Exosomal miR-92a-3p and miR-221-3p Could Predict the Response to First-Line Chemotherapy and Survival in Metastatic Colorectal Cancer. International Journal of Molecular Sciences (2023).
2. Rebound increase in microRNA levels at the end of 5-FU-based therapy in colorectal cancer patients. Scientific Reports (2023).
3. miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells. Nature Communications (2016).