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- Publisher Website: 10.1186/s12885-020-07081-z
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Article: MiR-34c downregulation leads to SOX4 overexpression and cisplatin resistance in nasopharyngeal carcinoma
Title | MiR-34c downregulation leads to SOX4 overexpression and cisplatin resistance in nasopharyngeal carcinoma |
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Authors | |
Keywords | miR-34c SOX4 TGFβ1 EMT Nasopharyngeal cancer |
Issue Date | 2020 |
Publisher | BioMed Central Ltd. The Journal's web site is located at http://www.biomedcentral.com/bmccancer/ |
Citation | BMC Cancer, 2020, v. 20 n. 1, p. article no. 597 How to Cite? |
Abstract | 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. |
Persistent Identifier | http://hdl.handle.net/10722/293220 |
ISSN | 2023 Impact Factor: 3.4 2023 SCImago Journal Rankings: 1.087 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Bissey, PA | - |
dc.contributor.author | Teng, M | - |
dc.contributor.author | Law, JH | - |
dc.contributor.author | Shi, W | - |
dc.contributor.author | Bruce, JP | - |
dc.contributor.author | Petit, V | - |
dc.contributor.author | Tsao, SW | - |
dc.contributor.author | Yip, KW | - |
dc.contributor.author | Liu, FF | - |
dc.date.accessioned | 2020-11-23T08:13:34Z | - |
dc.date.available | 2020-11-23T08:13:34Z | - |
dc.date.issued | 2020 | - |
dc.identifier.citation | BMC Cancer, 2020, v. 20 n. 1, p. article no. 597 | - |
dc.identifier.issn | 1471-2407 | - |
dc.identifier.uri | http://hdl.handle.net/10722/293220 | - |
dc.description.abstract | 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. | - |
dc.language | eng | - |
dc.publisher | BioMed Central Ltd. The Journal's web site is located at http://www.biomedcentral.com/bmccancer/ | - |
dc.relation.ispartof | BMC Cancer | - |
dc.rights | BMC Cancer. Copyright © BioMed Central Ltd. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject | miR-34c | - |
dc.subject | SOX4 | - |
dc.subject | TGFβ1 | - |
dc.subject | EMT | - |
dc.subject | Nasopharyngeal cancer | - |
dc.title | MiR-34c downregulation leads to SOX4 overexpression and cisplatin resistance in nasopharyngeal carcinoma | - |
dc.type | Article | - |
dc.identifier.email | Tsao, SW: gswtsao@hku.hk | - |
dc.identifier.authority | Tsao, SW=rp00399 | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.1186/s12885-020-07081-z | - |
dc.identifier.pmid | 32586280 | - |
dc.identifier.pmcid | PMC7318489 | - |
dc.identifier.scopus | eid_2-s2.0-85087140522 | - |
dc.identifier.hkuros | 319450 | - |
dc.identifier.volume | 20 | - |
dc.identifier.issue | 1 | - |
dc.identifier.spage | article no. 597 | - |
dc.identifier.epage | article no. 597 | - |
dc.identifier.isi | WOS:000545718700004 | - |
dc.publisher.place | United Kingdom | - |
dc.identifier.issnl | 1471-2407 | - |