A-to-I editing modifies the target and role of miR-376a-3p in papillary thyroid cancer.

Adenosine deaminase acting on RNA (ADAR)-mediated adenosine-to-inosine (A-to-I) RNA editing is of significant biological and clinical relevance in human tumors. Although papillary thyroid carcinoma (PTC) is frequently characterized as an "inert" tumor, it nonetheless presents a potential risk to human health. This study elucidates the regulatory mechanisms of both wild-type and modified microRNA-376a-3p (miR-376a-3p) in PTC. To assess miRNA and gene expression, RT-qPCR, Western blotting, and immunohistochemistry were employed. Functional assays included CCK-8, colony formation, 5-ethynyl-2'-deoxyuridine (EdU), wound healing, Transwell, and flow cytometry. Glycolytic activity was measured by glucose consumption, lactate production, extracellular acidification rate (ECAR), and oxygen consumption rate (OCR). Downstream targets were identified via dual-luciferase reporter assay. In PTC tissues, the A-to-I editing level of miR-376a-3p was elevated. ADAR2 (ADARB1) was identified as the principal editing enzyme, contributing to PTC carcinogenesis. Functionally, A-to-I editing switched miR-376a-3p from an anti-tumorigenic to an oncogenic molecule. At the molecular level, edited miR-376a-3p (ed-miR-376a-3p) acquired HOXD10 as a novel target while losing its interaction with KPNA4. Mechanistically, ed-miR-376a-3p enhanced glycolysis in PTC cells by downregulating HOXD10. ADAR2-mediated A-to-I editing confers an oncogenic role on miR-376a-3p by shifting its target from KPNA4 to HOXD10, thereby facilitating PTC tumorigenesis through enhanced glycolysis.