MiR-34c downregulation leads to SOX4 overexpression and cisplatin resistance in nasopharyngeal carcinoma

Background A 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, charac...

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Vydáno v:	BMC cancer Ročník 20; číslo 1; s. 597 - 13
Hlavní autoři:	Bissey, Pierre-Antoine, Teng, Mona, Law, Jacqueline H., Shi, Wei, Bruce, Jeff P., Petit, Valentin, Tsao, Sai W., Yip, Kenneth W., Liu, Fei-Fei
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London BioMed Central 26.06.2020 BioMed Central Ltd Springer Nature B.V BMC
Témata:	Antineoplastic agents Benzamides - pharmacology Biomedical and Life Sciences Biomedicine Biopsy Cancer metastasis Cancer Research Carcinoma Cell and molecular biology Cell cycle Cell Line, Tumor Cell viability Chemoradiotherapy Chemoresistance Chemotherapy Cisplatin Cisplatin - pharmacology Cisplatin - therapeutic use Dioxoles - pharmacology Down-Regulation Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics E-cadherin EMT Epithelial-Mesenchymal Transition - genetics Gene Expression Regulation, Neoplastic - drug effects Growth factors Health Promotion and Disease Prevention Humans Immunohistochemistry Lymphocytes Medicine/Public Health Mesenchyme Metastases Metastasis MicroRNA MicroRNAs MicroRNAs - genetics MicroRNAs - metabolism miR-34c miRNA Nasopharyngeal cancer Nasopharyngeal carcinoma Nasopharyngeal Carcinoma - drug therapy Nasopharyngeal Carcinoma - genetics Nasopharyngeal Carcinoma - mortality Nasopharyngeal Carcinoma - pathology Nasopharyngeal Neoplasms - drug therapy Nasopharyngeal Neoplasms - genetics Nasopharyngeal Neoplasms - mortality Nasopharyngeal Neoplasms - pathology Nasopharynx - pathology Oncology Overexpression Patients Prostate Radiation therapy Research Article RNA-Seq SOX4 SOXC Transcription Factors - genetics Stem cells Surgical Oncology TGFβ1 Throat cancer Transforming Growth Factor beta1 - antagonists & inhibitors Transforming Growth Factor beta1 - metabolism Transforming growth factor-b1 Transforming growth factors France United States > US TGFβ1 Nasopharyngeal cancer EMT SOX4 Cisplatin miR-34c
ISSN:	1471-2407, 1471-2407
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Shrnutí:	Background A 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. Methods Two 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. 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 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. TGFβ1 decreased miR-34c and increased SOX4 expression in vitro. The TGFβ 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. Conclusion miR-34c is downregulated in NPC. Repression of miR-34c was shown to increase SOX4 expression, which leads to cisplatin resistance, while TGFβ1 was found to repress miR-34c expression. Taken together, our study demonstrates that inhibition of the TGFβ1 pathway could be a strategy to restore cisplatin sensitivity in NPC.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1471-2407 1471-2407
DOI:	10.1186/s12885-020-07081-z