Unraveling the DUSP5/ERK/OXPHOS Axis: miR-92b-3p's Role in Lung Adenocarcinoma Progression and Metastasis.

Abstract

microRNA dysregulation plays a pivotal role in the tumorigenesis and metastasis of lung adenocarcinoma (LUAD). Building upon preliminary studies that identified miR-92b-3p as a potential diagnostic biomarker, this research elucidates its oncogenic mechanisms. Through the integration of cell functional assays, xenograft and metastasis models, dual-luciferase reporter assays, and western blot (WB) analysis, we demonstrate that the overexpression of miR-92b-3p significantly enhances the proliferation, invasion, and migration of LUAD cells. Moreover, LUAD cells overexpressing miR-92b-3p secrete increased levels of angiogenin, which significantly promotes angiogenesis, as evidenced by enhanced tube formation, migration, and invasion of human umbilical vein endothelial cells (HUVECs). By directly targeting and suppressing the tumor suppressor DUSP5, miR-92b-3p facilitates ERK phosphorylation, resulting in downstream activation of CREB and the induction of epithelial-mesenchymal transition (EMT). Metabolic profiling further revealed that miR-92b-3p concurrently enhances oxidative phosphorylation and ATP production, suggesting a putative positive feedback loop that may sustain ERK activation. Consequently, miR-92b-3p drives LUAD malignancy through two parallel functional axes: the DUSP5/ERK/OXPHOS signaling cascade promoting EMT and metabolic reprogramming, and the pro-angiogenic pathway mediated by enhanced angiogenin secretion. This dual regulatory network provides novel mechanistic insights into LUAD progression and nominates miR-92b-3p as a candidate target for further preclinical investigation.