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- W4255351918 abstract "Abstract Background: A major cause of disease-related death in nasopharyngeal carcinoma (NPC) is the development of distant metastasis (DM) despite combination chemo-radiotherapy. We have previously identified and validated a four micro-RNA (miRNA) signature which was prognostic for DM. In this study, characterization of a key component of this signature, miR-34c, revealed its role in chemotherapy resistance. Methods: 246 NPC patient biopsies samples were subject to comprehensive miRNA profiling and immunohistochemistry (IHC). Two human normal nasopharyngeal cell lines (immortalized; NP69 and NP460), as well as the NPC cell line C666-1, were used to generate pre-miR-34c (gain of function) and anti-miR-34c (loss of function) cells. Signaling pathways were assessed using quantitative real-time PCR (qRT-PCR) and Western blot. Cell viability was measured using the ATP lite assay. Results: MiR-34c was downregulated in NPC patient samples, and confirmed in vitro to directly target SOX4, a master regulator of epithelial-to-mesenchymal transition (EMT). MiR-34c downregulation triggered EMT-representative changes in NP69 and NP460; Snail, ZEB1, CDH2, and SOX2 were upregulated, while Claudin-1 and CDH1 were downregulated. Phenotypically, inhibition of miR-34c led to cisplatin resistance, whereas miR-34c over-expression sensitized NPC cells to cisplatin. TGFβ1 decreased miR-34c and increased SOX4 expression in vitro. The TGFβ receptor 1 inhibitor SB431542 reduced SOX4 expression and increased cisplatin sensitivity. Finally, immunohistochemistry revealed that in chemotherapy-treated NPC patients, lower SOX4 expression was associated with improved overall survival. Conclusion: Taken together, miR-34c downregulation correlates with higher incidence of DM; miR-34c also increases SOX4 expression which leads to cisplatin resistance. In association, TGFβ1 represses miR-34c expression, and inhibition of the TGFβ1 pathway is one strategy to restore cisplatin sensitivity in NPC." @default.
- W4255351918 created "2022-05-12" @default.
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- W4255351918 date "2019-09-12" @default.
- W4255351918 modified "2023-10-03" @default.
- W4255351918 title "MiR-34c Downregulation Leads to SOX4 Overexpression and Cisplatin Resistance in Nasopharyngeal Carcinoma" @default.
- W4255351918 doi "https://doi.org/10.21203/rs.2.14313/v1" @default.
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