Oncofetal IGF2BP3-mediated control of microRNA structural diversity in the malignancy of early-stage lung adenocarcinoma

Menée à partir d'échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome ou d'un carcinome épidermoïde du poumon et menée à partir d'échantillons pulmonaires sains, cette étude met en évidence un mécanisme par lequel la protéine oncofoetale IGF2BP3 favorise la production de certaines isoformes de microARNs

Résumé en anglais

Dysfunction of microRNAs (miRNAs) has been implicated in the pathogenesis of cancer and its principle is expected to be applicable for diagnosis. However, we do not know enough about the nature of miRNA dysfunction as an integrated cellular system. We show that oncofetal IGF2BP3 selectively regulates isoform production of miRNAs, resulting in significant changes in the cellular seed occupancy and structural component of cancer-related miRNAs, which contributes to the establishment of malignant gene expression profile. Thus, IGF2BP3-mediated isoform organization of miRNAs is proposed to be a critical cellular component of cancer progression. This principle allows the development of diagnostic biomarkers with a wide range of applications, including efficient prediction of the recurrence of early-stage lung adenocarcinoma. The nature of microRNA (miRNA) dysfunction in carcinogenesis remains controversial because of the complex connection between miRNA structural diversity and biological processes. Here, we found that oncofetal IGF2BP3 regulates the selective production of a subset of 3′-isoforms (3′-isomiRs), including miR-21-5p and Let-7 family, which induces significant changes in their cellular seed occupancy and structural components, establishing a cancer-specific gene expression profile. The D-score, reflecting dominant production of a representative miR-21-5p+C (a 3′-isomiR), discriminated between clinical early-stage lung adenocarcinoma (LUAD) cases with low and high recurrence risks, and was associated with molecular features of cell cycle progression, epithelial–mesenchymal transition pressure, and immune evasion. We found that IGF2BP3 controls the production of miR-21-5p+C by directing the nuclear Drosha complex to select the cleavage site. IGF2BP3 was also involved in the production of 3′-isomiRs of miR-425-5p and miR-454-3p. IGF2BP3-regulated these three miRNAs are suggested to be associated with the regulation of p53, TGF-β, and TNF pathways in LUAD. Knockdown of IGF2BP3 also induced a selective upregulation of Let-7 3′-isomiRs, leading to increased cellular Let-7 seed occupancy and broad repression of its target genes encoding cell cycle regulators. The D-score is an index that reflects this cellular situation. Our results suggest that the aberrant regulation of miRNA structural diversity is a critical component for controlling cellular networks, thus supporting the establishment of a malignant gene expression profile in early stage LUAD.