Our original microRNA (miRNA) expression signatures (based on RNA sequencing) revealed that both strands of the miR-145 duplex (miR-145-5p, the guide strand, and miR-145-3p, the passenger strand) were downregulated in several types of cancer tissues. Involvement of passenger strands of miRNAs in cancer pathogenesis is a new concept in miRNA biogenesis. In our continuing analysis of lung adenocarcinoma (LUAD) pathogenesis, we aimed here to identify important oncogenes that were controlled by miR-145-5p and miR-145-3p. Downregulation of miR-145-5p and miR-145-3p was confirmed in LUAD clinical specimens. Functional assays showed that miR-145-3p significantly blocked the malignant abilities in LUAD cells, e.g., cancer cell proliferation, migration and invasion. Thus, the data showed that expression of the passenger strand of the miR-145-duplex acted as an anti-tumor miRNA. In LUAD cells, we identified four possible target genes (LMNB2, NLN, SIX4, and DDC) that might be regulated by both strands of miR-145. Among the possible targets, high expression of LMNB2 predicted a significantly poorer prognosis of LUAD patients (disease-free survival, p = 0.0353 and overall survival, p = 0.0017). Overexpression of LMNB2 was detected in LUAD clinical specimens and its aberrant expression promoted malignant transformation of LUAD cells. Genes regulated by anti-tumor miR-145-5p and miR-145-3p are closely involved in the molecular pathogenesis of LUAD. We suggest that they are promising prognostic markers for this disease. Our approach, based on the roles of anti-tumor miRNAs, will contribute to improved understanding of the molecular pathogenesis of LUAD.
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The present study was supported by KAKENHI grants 17K09660 and 18K09338.
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The authors declare that they have no conflict of interest.
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Misono, S., Seki, N., Mizuno, K. et al. Dual strands of the miR-145 duplex (miR-145-5p and miR-145-3p) regulate oncogenes in lung adenocarcinoma pathogenesis. J Hum Genet 63, 1015–1028 (2018). https://doi.org/10.1038/s10038-018-0497-9
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