Abstract
Human nasopharyngeal carcinoma (NPC) has the highest metastatic rate in head and neck. However, the mechanisms underlying NPC metastasis remain unclear. Here using propensity-score-matched miRNA microarray analysis, miR-142-3p is identified to be the most correlated with distant-metastasis-free survival and downregulated in paraffin-embedded NPC with distant metastasis, which is validated in both internal cohort and external GEO dataset from Canada. miR-142 locus hypermethylation was observed and found to be associated with miR-142-3p downregulation in metastatic NPC. Furthermore, miR-142-3p was epigenetically silenced by EZH2-recruited DNMT1 and suppressed NPC cell metastasis and EMT. Intersecting PCR array gene profiling with bioinformatic prediction, we identify ZEB2 as a direct and functional target of miR-142-3p in NPC. Reversal of miR-142-3p silencing efficiently suppresses NPC cell invasion and metastasis. Moreover, epigenetic miR-142 hypermethylation is correlated with unfavorable prognosis in both training and validation cohorts. This study identifies miR-142-3p as a key suppressive regulator in NPC metastasis and reveals a DNMT1-mediated epigenetic mechanism for miR-142-3p silencing, providing a potential prognostic marker and therapeutic target to combat NPC metastasis.
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Acknowledgements
We would like to thank Hanqi Yin (Guangdong Longsee Biomedical Corporation, China) for bioinformatics and statistical consultation and Professor Musheng Zeng for cell lines.
Funding
This study was supported by grants from the National Natural Science Foundation of China (81402516, 81773229), Guangdong Special Support Program (2017TQ04R754), Natural Science Foundation of Guangdong Province (2018B030306045, 2017A030312003), Health & Medical Collaborative Innovation Project of Guangzhou City, China (201803040003), Innovation Team Development Plan of the Ministry of Education (No. IRT_17R110), and Overseas Expertise Introduction Project for Discipline Innovation (111 Project, B14035).
Author contributions
YL, JM and NL designed the experiments. YL, QH, XW, XH and XY conducted experiments and acquiring data. YL, XH, XY, XT, PZ, YL and YS analyzed the data. QH, YW and JZ provided reagents. YL, JM and NL wrote the manuscript. All authors read and approved the final manuscript.
Data availability
The microarray datasets used in this paper have been deposited at Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under the series accession number GSE32960 and GSE70970. The authenticity of this article has been validated by uploading the key raw data onto the Research Data Deposit public platform (http://www.researchdata.org.cn), with the approval RDD number as RDDB2018000218.
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All animal studies were approved by the Institutional Animal Care and Use Ethics Committee of Sun Yat-sen University Cancer Center (approval number: L102012015090I). The experimental methods comply with the Helsinki Declaration.
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Li, Y., He, Q., Wen, X. et al. EZH2-DNMT1-mediated epigenetic silencing of miR-142-3p promotes metastasis through targeting ZEB2 in nasopharyngeal carcinoma. Cell Death Differ 26, 1089–1106 (2019). https://doi.org/10.1038/s41418-018-0208-2
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DOI: https://doi.org/10.1038/s41418-018-0208-2
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