miR34a

miR-34a is a microRNA encoded by the MIR34A gene in humans. It is the most studied member of the miR-34 family and is often described as a tumor suppressor microRNA. The MIR34A gene is located on chromosome 1p36, while its family members, miR-34b and miR-34c, are produced from a separate locus on chromosome 11q23.

miR-34a is transcribed by RNA polymerase II, processed by Drosha and Dicer to generate the mature molecule, and is incorporated into the RNA-induced silencing complex. Expression of miR-34a is transcriptionally activated by p53 in response to cellular stress, creating a positive feedback loop that enhances p53 activity.

miR-34a acts by binding to complementary sequences in the 3' UTR of target mRNAs, leading to translational repression or mRNA degradation. Important targets include BCL2 (apoptosis), CDK4 and CDK6 and Cyclin D1 (cell cycle), MET, and NOTCH1, as well as SIRT1, which modulates p53 activity. Through these targets, miR-34a promotes cell cycle arrest, senescence, and apoptosis, and can suppress epithelial-mesenchymal transition (EMT) and cancer stem cell properties.

Clinical significance: miR-34a is downregulated or silenced in various cancers due to promoter methylation, deletion, or defective p53 signaling. Restoration of miR-34a can inhibit tumor growth in preclinical models; thus it has been explored as a therapeutic candidate. In 2013-2016, a liposome-formulated miR-34a mimic (MRX34) entered a clinical trial but was halted due to immune-related adverse events and the program was discontinued. Research continues on delivery methods and safety. miR-34a levels have also been investigated as potential biomarkers in several cancer types.

Beyond cancer, miR-34a participates in development and cellular senescence and has been linked to aging and metabolic regulation.