Abstract 1188: Understanding the malignant properties of early-stage lung adenocarcinoma through oncofetal IGF2BP3-mediated miRNA structural diversity

Abstract Although functional abnormalities in microRNAs, a class of small non-coding RNAs, have been implicated in the pathogenesis of various cancer types, the nature of their dysfunction as an integrated cellular system remains poorly understood. Here, we demonstrate that the oncofetal protein IGF2BP3 selectively regulates the production of 3’-isoforms (3’-isomiRs), including miR-21-5p and members of the Let-7 family. This regulation induces significant changes in their cellular seed occupancy and structural composition, thereby establishing a cancer-specific gene expression profile. Notably, the D-score, which reflects the dominant production of miR-21-5p+C (a representative 3'-isomiR), effectively discriminates between early-stage lung adenocarcinoma (LUAD) cases with low and high recurrence risks. This score is also associated with molecular features indicative of cell cycle progression, epithelial-mesenchymal transition pressure, and immune evasion. Mechanistically, we found that IGF2BP3 directs the nuclear Drosha complex to select specific cleavage sites, thereby controlling the production of miR-21-5p+C. IGF2BP3 also modulates the 3’-isomiRs of miR-425-5p and miR-454-3p, which are implicated in the regulation of p53, TGF-β, and TNF pathways in LUAD. Furthermore, IGF2BP3 selectively represses the production of 3’-isomiRs from the Let-7 family, reducing their seed occupancy and subsequently altering the expression of Let-7 target genes involved in cell cycle regulation. These findings suggest that IGF2BP3-mediated miRNA isoform organization constitutes a critical component of cancer progression (Fujiwara et al. PNAS 2024). This principle provides a foundation for developing diagnostic biomarkers with broad applications, including the efficient prediction of early-stage LUAD recurrence. Citation Format: Naoto Tsuchiya, Yuko Fujiwara, Ryou-u Takahashi, Motonobu Saito, Akiteru Goto. Understanding the malignant properties of early-stage lung adenocarcinoma through oncofetal IGF2BP3-mediated miRNA structural diversity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1188.