DLK1-DIO3 region as a source of tumor suppressor miRNAs in papillary thyroid carcinoma

• Published in: Translational oncology 2024-08, Vol.46, p.101849, Article 101849
• Main Authors: Alves, Letícia Ferreira, Marson, Leonardo Augusto, Sielski, Micheli Severo, Vicente, Cristina Pontes, Kimura, Edna Teruko, Geraldo, Murilo Vieira
• Format: Article
• Language: English
• Subjects: DLK1-DIO3 region; MicroRNA; miR-485–5p; Original Research; Papillary thyroid cancer
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2023.101849

•miRNAs from DLK1-DIO3 are globally down regulated in papillary thyroid carcinomas.•Only twelve, out of 100 mature miRNAs, are responsible for most of the impact of DLK1-DIO3 region on the post transcriptional regulation in PTC.•DLK1-DIO3-derived miRNAs act predominantly in PTC tumor progression.•In vitro functional analises show influence of miR-485–5p on cell migration, invasion and EMT.•miR-485–5p action is dependent on the tumor oncogenic background, with effect only in BRAF-mutant papillary thyroid carcinoma cell line. In previous studies, we demonstrated the downregulation of several miRNAs from the DLK1-DIO3 genomic region in papillary thyroid carcinoma (PTC). Due to the large number of miRNAs within this region, the individual contribution of these molecules to PTC development and progression remains unclear. In this study, we aimed to clarify the contribution of DLK1-DIO3-derived miRNAs to PTC. We used different computational approaches and in vitro resources to assess the biological processes and signaling pathways potentially modulated by these miRNAs. Our analysis suggests that, out of more than 100 mature miRNAs originated from the DLK1-DIO3 region, a set of 12 miRNAs accounts for most of the impact on PTC development and progression, cooperating to modulate distinct cancer-relevant biological processes, such as cell migration, extracellular matrix remodeling, and signal transduction. The restoration of the expression of one of these miRNAs (miR-485–5p) in a BRAFT199A-positive PTC cell line impaired proliferation and migration, suppressing the expression of GAB2 and RAC1, validated miR-485–5p targets. Overall, our results shed light on the role of the DLK1-DIO3 region, which harbors promising tumor suppressor miRNAs in thyroid cancer, and open prospects for the functional exploration of these miRNAs as therapeutic targets for PTC.