Journal
BMC CANCER
Volume 20, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12885-020-07081-z
Keywords
miR-34c; SOX4; TGF beta 1; EMT; Nasopharyngeal cancer; Cisplatin
Categories
Funding
- Canadian Institutes for Health Research [PJT -153289]
- Peter and Shelagh Godsoe Chair in Radiation Medicine
- Mariano Elia Chair in Head AMP
- Neck Cancer Research
- Campbell Family Institute for Cancer Research
- Ministry of Health and Long-Term Care
- Princess Margaret Cancer Centre Head AMP
- Neck Translational Program
- Health AMP
- Medical Research Fund (Hong Kong) [04151726]
- Research Grant Council (Hong Kong) [C7027-16G]
- philanthropic fund from the Wharton Family
- philanthropic fund from the Joe's Team
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BackgroundA major cause of disease-related death in nasopharyngeal carcinoma (NPC) is the development of distant metastasis (DM) despite combination chemoradiotherapy treatment. We previously identified and validated a four microRNA (miRNA) signature that is prognostic for DM. In this study, characterization of a key component of this signature, miR-34c, revealed its role in chemotherapy resistance.MethodsTwo hundred forty-six NPC patient biopsy 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 for miR-34c gain-of-function and loss-of-function experiments. Signaling pathways were assessed using quantitative real-time PCR (qRT-PCR) and Western blot. Cell viability was measured using the ATPlite assay.ResultsMiR-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 whereby 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. TGF beta 1 decreased miR-34c and increased SOX4 expression in vitro. The TGF beta receptor 1 inhibitor SB431542 reduced SOX4 expression and increased cisplatin sensitivity. Finally, IHC revealed that lower SOX4 expression was associated with improved overall survival in chemotherapy-treated NPC patients.ConclusionmiR-34c is downregulated in NPC. Repression of miR-34c was shown to increase SOX4 expression, which leads to cisplatin resistance, while TGF beta 1 was found to repress miR-34c expression. Taken together, our study demonstrates that inhibition of the TGF beta 1 pathway could be a strategy to restore cisplatin sensitivity in NPC.
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