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  • Title: miR-16-5p regulates aerobic glycolysis and tumorigenesis of NSCLC cells via LDH-A/lactate/NF-κB signaling.
    Author: Arora S, Singh P, Tabassum G, Dohare R, Syed MA.
    Journal: Life Sci; 2022 Sep 01; 304():120722. PubMed ID: 35714705.
    Abstract:
    BACKGROUND AND AIM: Cancer cells exhibit Warburg effect, characterized by increased glycolysis followed by fermentative conversion of pyruvate to lactate. Upregulation of Lactate Dehydrogenase-A (LDH-A) is elucidated to be a dominant molecular mediator of the phenomenon. Also, microRNA (miRNA) dysregulation participates in malignant progression and dissemination in several cancers. miR-16-5p is considerably reduced in lung cancers (LC), suggesting its tumor-suppressive role. However, its role in the regulation of aerobic glycolysis remains unknown. Our study aims to identify the regulatory roles of miR-16-5p/LDH-A in Non-small cell lung cancer (NSCLC). MAIN METHODS: We evaluated the differential expression of LDH-A and its prognostic potential in NSCLC tissues using online databases. We performed Tissue analysis using Immunohistochemistry (IHC); In-vitro cellular analysis including transient transfection, cellular proliferation, migration, and colony forming analysis. We also performed cell survival, metabolic, cell cycle, apoptotic, ROS generation and Immunocytochemistry (ICC) analyses to identify the role of miR-16-5p/LDH-A in aerobic glycolysis and tumorigenesis of NSCLC. KEY FINDINGS: We have identified that miR-16-5p directly targets LDH-A by binding to the complementary binding regions present in its 3'-UTR region, leading to degradation, sequentially leading to reduced lactate accumulation, glucose uptake and ATP levels. Our study also demonstrated the role of lactate accumulation in promoting NSCLC tumorigenesis via activation of NF-κB signaling pathway. However, miR-16-5p mediated targeting of LDH-A downregulates the expression of NF-κB associated genes, along with increased ROS generation, apoptosis, and cell cycle arrest. SIGNIFICANCE: In conclusion, our findings identify miR-16-5p/LDH-A/lactate/NF-κB as an important link between metabolism and NSCLC cells tumorigenesis.
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