Abstract

The tissue inhibitor of metalloproteinase-3 (TIMP3) is the only member of the TIMP family that binds to the extracellular matrix and suppresses cancer cell growth, angiogenesis, migration, and invasion. However, whether the abnormal expression and promoter methylation of TIMP3 facilitates oral cancer metastasis remain unclear. In this study, the DNA methylation levels of TIMP3 CpG islands were assessed through pyrosequencing. Artificial modulation of TIMP3 was performed to explore the role of TIMP3 in tumor metastasis in vitro and in vivo. Our results showed that the suppression of TIMP3 transcription by DNA methylation involves the inhibition of the binding of the transcription factor Sp1 to the TIMP3 promoter as well as the upregulation of DNMT1 and DNMT3B. Functional analyses revealed that TIMP3 overexpression reduced migration and invasion abilities in oral cancer cells and inhibited lymph node metastasis in vivo. Moreover, TIMP3 regulated epithelial–mesenchymal transition by increasing the expression of the epithelial markers and reducing the expression of the mesenchymal markers. In conclusion, our findings suggested that the suppression of TIMP3 by DNA methylation contributes to oral cancer metastasis.

Details

Title
Loss of TIMP3 by promoter methylation of Sp1 binding site promotes oral cancer metastasis
Author
Chun-Wen, Su 1 ; Yu-Chao, Chang 2 ; Ming-Hsien Chien 3   VIAFID ORCID Logo  ; Yi-Hsien Hsieh 4 ; Mu-Kuan, Chen 5 ; Chiao-Wen, Lin 6 ; Yang, Shun-Fa 1   VIAFID ORCID Logo 

1  Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan 
2  School of Dentistry, Chung Shan Medical University, Taichung, Taiwan; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan 
3  Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 
4  Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan 
5  Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Otorhinolaryngology-Head and Neck Surgery, Changhua Christian Hospital, Changhua, Taiwan 
6  Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan; Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan 
Pages
1-17
Publication year
2019
Publication date
Oct 2019
Publisher
Springer Nature B.V.
e-ISSN
20414889
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41419-019-2016-0
ProQuest document ID
2306483336
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.