由于 miRNA 结构多样性与生物过程之间的复杂联系，致癌过程中 microRNA (miRNA) 功能障碍的性质仍然存在争议。在这里，我们发现肿瘤胎儿 IGF2BP3 调节 3'-亚型 (3'-isomiR) 子集的选择性产生，包括 miR-21-5p 和 Let-7 家族，这会诱导其细胞种子占有率和结构成分发生显着变化，建立癌症特异性基因表达谱。 D 评分反映了代表性 miR-21-5p C（a 3'-isomiR）的显着产生，区分了具有低复发风险和高复发风险的临床早期肺腺癌 (LUAD) 病例，并且与分子特征相关细胞周期进展、上皮间质转化压力和免疫逃避。我们发现 IGF2BP3 通过指导核 Drosha 复合物选择切割位点来控制 miR-21-5p C 的产生。 IGF2BP3 还参与 miR-425-5p 和 miR-454-3p 3'-isomiR 的产生。 IGF2BP3 调节的这三种 miRNA 被认为与 LUAD 中 p53、TGF-β 和 TNF 通路的调节有关。 IGF2BP3 的敲低还诱导 Let-7 3'-isomiR 的选择性上调，导致细胞 Let-7 种子占有率增加并广泛抑制其编码细胞周期调节因子的靶基因。 D-score 是反映这种细胞情况的指数。我们的结果表明，miRNA 结构多样性的异常调控是控制细胞网络的关键组成部分，从而支持在早期 LUAD 中建立恶性基因表达谱。

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.