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Overcoming cisplatin resistance in osteosarcoma through the miR-199a-modulated inhibition of HIF-1α
Dysregulation of miRNAs has been shown to contribute to multiple tumorigenic processes, as well as to correlate with tumour progression and prognosis. miR-199a has been shown to be dysregulated in multiple tumour types. However, the association between miR-199a and the chemoresistance features of os...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859113/ https://www.ncbi.nlm.nih.gov/pubmed/28442599 http://dx.doi.org/10.1042/BSR20170080 |
Sumario: | Dysregulation of miRNAs has been shown to contribute to multiple tumorigenic processes, as well as to correlate with tumour progression and prognosis. miR-199a has been shown to be dysregulated in multiple tumour types. However, the association between miR-199a and the chemoresistance features of osteosarcoma are not well understood, the target genes for miR-199a and the regulatory mechanisms are also unknown. In the present study, we demonstrated that miR-199a is expressed at low levels in osteosarcoma cells and patient samples. By the selection and establishment of cisplatin resistant osteosarcoma cell line, we observed a correlation between miR-199a and cisplatin resistance in osteosarcoma cells: resistant cells exhibit attenuated miR-199a expressions and exogenous overexpression of miR-199a sensitizes osteosarcoma cells to cisplatin. Moreover, we identified HIF-1α as a direct target for miR-199a. Intriguingly, cisplatin resistant osteosarcoma cells display significantly elevated HIF-1α expression under hypoxia. We report here overexpression of miR-199a resensitizes cisplatin resistant cells to cisplatin through inhibition of HIF-1α in vitro and in vivo. Finally, by analysing the clinical osteosarcoma patient samples, we demonstrate a reverse correlation between miR-199a and HIF-1α mRNAs. Our study will provide mechanisms for the miRNA-mediated anticancer therapy and miR-199a may be considered a promising therapeutic agent for osteosarcoma patients who fail to respond to conventional chemotherapy. |
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