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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. [ABSTRACT FROM AUTHOR]

Sarcoma is a rare mesenchymal malignancy that comprises more than 50 histological subtypes. Because of the rarity and diversity of sarcomas, their differential diagnosis is difficult, and there is still a need for biomarkers to support pathological diagnoses. Micro RNAs (miRNAs) are small noncoding RNAs that regulate the behavior of tumors, such as invasion and metastasis. The expression patterns of miRNAs reflect the origin of malignancy and are considered to be candidate biomarkers. To understand the molecular background of those histological subtypes, we investigated the miRNA expression in 89 tumor tissues of eight subtypes. The correlation coefficients between each sarcoma subtype on the basis of miRNA expression values were mostly higher than 0.7, reflecting the common mesenchymal origin. By contrast, hierarchical clustering and principal component analysis showed that three types of sarcoma with chromosomal translocation (i.e., dermatofibrosarcoma protuberans, myxoid liposarcoma, and synovial sarcoma) were grouped according to their histological subtypes, whereas five types with complex karyotypes (i.e., myxofibrosarcoma, malignant peripheral nerve sheath tumor, undifferentiated pleomorphic sarcoma, dedifferentiated liposarcoma, and pleomorphic liposarcoma) were not. Notably, the number of miRNAs whose expression pattern was unique to histological subtypes with statistical significance was higher in sarcomas with chromosome translocation than in those with complex karyotypes. Hence, it can be concluded that the miRNAs unique to histological subtypes are candidate biomarkers for the differential diagnosis of sarcomas, particularly in those with chromosomal translocation. [ABSTRACT FROM AUTHOR]