Exploring LAT-derived miRNAs as regulatory agents of EphrinA3 in glioblastoma multiforme.

BACKGROUND: This study focuses on the findings related to Latency- Associated Transcript (LAT)- derived miRNAs and their interactions with ephrin family genes, especially EFNA3. It contextualizes, these results within the broader Glioblastoma multiform (GBM) research landscape. METHOD: The differential expression of the Ephrin (EFN) family in GBM was analyzed using TCGA and GEO databases, alongside survival data from the Kaplan-Meier Plotter. Bioinformatics predicted LAT-derived miRNAs targeting EFN genes, which were validated in vitro. Luciferase assays confirmed miR-H2 and miR-H3's targeting of EFNA3, while qRT-PCR and Western blotting assessed their effects on mRNA and protein levels. RESULTS: EphrinA3 is significantly overexpressed in GBM tissues, and its expression level is correlated with the prognosis of GBM patients. Both miR-H2-3p and miR-H3-3p effectively target EphrinA3, resulting in approximately a twofold reduction in luciferase activity when assessed individually. Notably, this suppressive effect is enhanced fourfold in cells expressing LAT transcript. Furthermore, both miRNAs significantly downregulate EFNA3 expression at both the mRNA and protein levels. Loss-of-function experiments indicate that LAT-derived miRNAs play a critical regulatory role in modulating EFNA3 expression. CONCLUSION: The study highlights the potential of targeting EphrinA3 through HSV-1-derived miRNAs, particularly miR-H2 and miR-H3, as a promising therapeutic strategy. These findings suggest that modulating EphrinA3 expression could enhance treatment efficacy while minimizing off-target effects, paving the way for innovative approaches to combat GBM. Further research is warranted to explore the clinical implications of these insights in developing effective therapies for this aggressive cancer.