Multi‐Omics and Functional Analyses Identify let‐7b‐3p as a Negative Regulator of EMT in Lung Adenocarcinoma

Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC), and its malignant progression involves complex molecular mechanisms. While microRNAs (miRNAs) play a crucial regulatory role in LUAD development, their specific mechanisms remain unclear. This study used bioinformatics analysis to identify key miRNA-mRNA interaction axes in LUAD, revealing that let-7b-3p was significantly downregulated. Functional analyses demonstrated that let-7b-3p regulates LUAD cell proliferation, migration, and invasion by targeting High Mobility Group AT-Hook 2 (HMGA2) and Lin-28 Homolog A (LIN28A). Dual-luciferase reporter assays confirmed that let-7b-3p directly binds to HMGA2 and LIN28A, suppressing their expression. Furthermore, Western blot and immunofluorescence (IF) assays showed that let-7b-3p inhibits the Wnt/TGF-β signaling pathway and epithelial-mesenchymal transition (EMT) via the HMGA2-LIN28A axis. In vivo, experiments using a nude mouse model further demonstrated that let-7b-3p overexpression significantly suppressed LUAD tumor growth and lung metastasis while reducing the expression of EMT-related molecules. Importantly, this study is the first to reveal the inhibitory role of let-7b-3p in LUAD through the HMGA2-LIN28A axis in regulating the Wnt/TGF-β signaling pathway and EMT. These findings highlight the originality of this work and underscore the potential clinical translational value of targeting let-7b-3p or the HMGA2-LIN28A axis as novel therapeutic strategies for LUAD.