Dual role of mir-146a in non-small cell lung cancer progression: Molecular mechanisms and clinical potential

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality. 2.48 million new cases were reported globally in 2022, driven by rising adenocarcinoma rates linked to environmental factors such as air pollution. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression by targeting messenger RNA for degradation or translational repression. Emerging studies highlight miR-146a as a molecular pivot with dual functionality that acts as a tumor suppressor by inhibiting NF-κB signaling to reduce inflammation and chemoresistance while paradoxically exhibiting oncogenic potential through immune modulation in specific microenvironments. The expression of miR-146a has been associated with numerous pathological and physiological alterations in cancer cells, including the modulation of various signaling pathways such as TNF-α, NF-κB, MEK-1/2, and JNK-1/2. miR-146a can act exogenously through extracellular vesicles and thereby reprogram tumor-associated macrophages to either promote or inhibit metastasis depending on cellular context. The diagnostic potential of miR-146a is underscored by expression patterns correlating with disease progression and treatment response in NSCLC, whilst preclinical studies suggest therapeutic promise when combined with checkpoint inhibitors. In this review, we first discuss the biogenesis and function of miR-146a in NSCLC development, with emphasis on recent findings that underscore the dual role of miR-146a in the regulation of cell proliferation, invasion, inflammation, immune responses, and chemoresistance in NSCLC. We also describe the possible function of miR-146a as a biomarker for cancer diagnosis, prognosis, and therapeutic target.