miRNA-7 and miRNA-324-5p regulate alpha9-Integrin expression and exert anti-oncogenic effects in rhabdomyosarcoma

• Published in: Cancer letters 2020-05, Vol.477, p.49-59
• Main Authors: Molist, C., Navarro, N., Giralt, I., Zarzosa, P., Gallo-Oller, G., Pons, G., Magdaleno, A., Moreno, L., Guillén, G., Hladun, R., Garrido, M., Soriano, A., Segura, M.F., Sánchez de Toledo, J., Gallego, S., Roma, J.
• Format: Article
• Language: English
• Subjects: Adapter proteins; Animals; Antibodies; Brain cancer; Cell adhesion & migration; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Chromosomes; Cloning; Colonization; Doxycycline - pharmacology; Focal Adhesion Kinase 1 - genetics; Focal Adhesion Kinase 1 - metabolism; Gene Expression Regulation, Neoplastic; Humans; Integrins; Integrins - genetics; Invasiveness; ITGA9; Kinases; Laboratories; Ligands; Medical prognosis; Melanoma; Metastases; Metastasis; Mice, SCID; MicroRNAs; MicroRNAs - genetics; miRNA; Pediatric cancer; Pediatrics; Phosphorylation; Prognosis; Rhabdomyosarcoma; Rhabdomyosarcoma - drug therapy; Rhabdomyosarcoma - genetics; Rhabdomyosarcoma - pathology; RNA, Small Interfering; Soft tissue sarcoma; Xenograft Model Antitumor Assays
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2020.02.035

The prognosis of patients with metastatic rhabdomyosarcoma (RMS), the most common type of soft tissue sarcoma in children, is poor and no strategies have been identified to improve their dismal prognosis. Alpha-9 integrin (ITGA9) plays a particularly crucial role in cancer progression and invasiveness. Despite the consensus on the remarkable pro-oncogenic potential of this protein, the miRNA-mediated regulation of ITGA9 has barely been studied to date. In the present study, miR-7 and miR-324-5p were selected as the best candidates after a screening to find ITGA9 regulators, and their effects on cell proliferation and invasion in RMS are described and characterized for the first time. Interestingly, the overexpression of both miRNA produced a clear impairment of cell proliferation, while miR-7 also induced a remarkable drop in cell invasion. Furthermore, the stable overexpression of both miRNA was found to reduce tumor growth in orthotopic RMS models and miR-7 was able to impair metastatic lung colonization. Consequently, we conclude that miR-7 and miR-324-5p show anti-oncogenic and anti-metastatic potential, thereby opening up the possibility of being used as novel therapeutic tools to avoid RMS progression. [Display omitted] •miR-7 and miR-324-5p are described for the first time as ITGA9 regulators in RMS.•miR-7 and miR-324-5p have a clear role in cell proliferation.•miR-7 has a crucial role in cell invasion, both in vitro and in vivo.•The animal models provided confirms a crucial in vivo role of both miRNA.