The Modulatory Role of MicroRNA-873 in the Progression of KRAS-Driven Cancers
| Autor: | Bulent Ozpolat, Tamer M. Abdelghany, Stephen T. C. Wong, Kubra Karagoz, Nermin Kahraman, Recep Bayraktar, Michael L. Gatza, Nashwa N. Kabil, Ahmed Ashour, Hamada Ahmed Mokhlis, Abdel Aziz H. Abdel Aziz, Jianting Sheng, Gabriel Lopez-Berestein, Ayşe Caner, Cristian Rodriguez-Aguayo, Erika P. Zambalde, Pinar Kanlikilicer, George A. Calin |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
liposomes endocrine system diseases proliferation non-coding RNA pancreatic cancer Biology miR-873 medicine.disease_cause Article 03 medical and health sciences gene silencing 0302 clinical medicine breast cancer oncogene Pancreatic cancer Drug Discovery microRNA medicine KRAS Gene silencing PI3K/AKT/mTOR pathway Triple-negative breast cancer therapy Oncogene lcsh:RM1-950 medicine.disease invasion ncRNA digestive system diseases tumorigenesis lcsh:Therapeutics. Pharmacology 030104 developmental biology 030220 oncology & carcinogenesis Cancer research triple-negative breast cancer Molecular Medicine nanoparticles Carcinogenesis gene regulation |
| Zdroj: | Molecular Therapy. Nucleic Acids Molecular Therapy: Nucleic Acids, Vol 14, Iss, Pp 301-317 (2019) |
| ISSN: | 2162-2531 |
| Popis: | KRAS is one of the most frequently mutated proto-oncogenes in pancreatic ductal adenocarcinoma (PDAC) and aberrantly activated in triple-negative breast cancer (TNBC). A profound role of microRNAs (miRNAs) in the pathogenesis of human cancer is being uncovered, including in cancer therapy. Using in silico prediction algorithms, we identified miR-873 as a potential regulator of KRAS, and we investigated its role in PDAC and TNBC. We found that reduced miR-873 expression is associated with shorter patient survival in both cancers. miR-873 expression is significantly repressed in PDAC and TNBC cell lines and inversely correlated with KRAS levels. We demonstrate that miR-873 directly bound to the 3′ UTR of KRAS mRNA and suppressed its expression. Notably, restoring miR-873 expression induced apoptosis; recapitulated the effects of KRAS inhibition on cell proliferation, colony formation, and invasion; and suppressed the activity of ERK and PI3K/AKT, while overexpression of KRAS rescued the effects mediated by miR-873. Moreover, in vivo delivery of miR-873 nanoparticles inhibited KRAS expression and tumor growth in PDAC and TNBC tumor models. In conclusion, we provide the first evidence that miR-873 acts as a tumor suppressor by targeting KRAS and that miR-873-based gene therapy may be a therapeutic strategy in PDAC and TNBC. Keywords: KRAS, oncogene, non-coding RNA, microRNA, ncRNA, miR-873, proliferation, invasion, gene regulation, tumorigenesis, gene silencing, therapy, nanoparticles, pancreatic cancer, liposomes, breast cancer, triple-negative breast cancer |
| Databáze: | OpenAIRE |
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