Cargando…
Inhibiting the redox function of APE1 suppresses cervical cancer metastasis via disengagement of ZEB1 from E-cadherin in EMT
BACKGROUND: Metastasis is a major challenge in cervical cancer treatment. Previous studies have shown that the dual functional protein apurinic/apyrimidinic endonuclease 1 (APE1) promotes tumor metastasis and is overexpressed in cervical cancer. However, the biological role and mechanism of APE1 in...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246661/ https://www.ncbi.nlm.nih.gov/pubmed/34210327 http://dx.doi.org/10.1186/s13046-021-02006-5 |
_version_ | 1783716356688969728 |
---|---|
author | Li, Qing Zhou, Zhi-Wei Duan, Wei Qian, Cheng-Yuan Wang, Shu-Nan Deng, Meng-Sheng Zi, Dan Wang, Jian-Min Mao, Cheng-Yi Song, Guanbin Wang, Dong Westover, Kenneth D. Xu, Cheng-Xiong |
author_facet | Li, Qing Zhou, Zhi-Wei Duan, Wei Qian, Cheng-Yuan Wang, Shu-Nan Deng, Meng-Sheng Zi, Dan Wang, Jian-Min Mao, Cheng-Yi Song, Guanbin Wang, Dong Westover, Kenneth D. Xu, Cheng-Xiong |
author_sort | Li, Qing |
collection | PubMed |
description | BACKGROUND: Metastasis is a major challenge in cervical cancer treatment. Previous studies have shown that the dual functional protein apurinic/apyrimidinic endonuclease 1 (APE1) promotes tumor metastasis and is overexpressed in cervical cancer. However, the biological role and mechanism of APE1 in cervical cancer metastasis have rarely been studied. METHODS: We used gene set enrichment analysis (GSEA) to determine the APE1-related signaling pathways in cervical cancer. To investigate the role and mechanism of APE1 in cervical cancer metastasis and invasion, immunohistochemistry, immunofluorescence, western blotting, secondary structure prediction, coimmunoprecipitation, luciferase reporter, and electrophoretic mobility shift assays were performed. The inhibitory effects of the APE1 redox function inhibitor APX3330 on cervical cancer metastasis were evaluated using animal models. RESULTS: Clinical data showed that high expression of APE1 was associated with lymph node metastasis in cervical cancer patients. GSEA results showed that APE1 was associated with epithelial to mesenchymal transition (EMT) in cervical cancer. Ectopic expression of APE1 promoted EMT and invasion of cervical cancer cells, whereas inhibition of APE1 suppressed EMT and invasion of cervical cancer cells in a redox function-dependent manner. Notably, APE1 redox function inhibitor APX3330 treatment dramatically suppressed cervical cancer cell lymph node and distant metastasis in vivo. Furthermore, we found that APE1 enhanced the interaction between ZEB1 and the E-cadherin promoter by binding to ZEB1, thereby suppressing the expression of E-cadherin, a negative regulator of EMT. CONCLUSION: Our findings help to elucidate the role played by APE1 in cervical cancer metastasis and targeting APE1 redox function may be a novel strategy for inhibiting cervical cancer metastasis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-02006-5. |
format | Online Article Text |
id | pubmed-8246661 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-82466612021-07-06 Inhibiting the redox function of APE1 suppresses cervical cancer metastasis via disengagement of ZEB1 from E-cadherin in EMT Li, Qing Zhou, Zhi-Wei Duan, Wei Qian, Cheng-Yuan Wang, Shu-Nan Deng, Meng-Sheng Zi, Dan Wang, Jian-Min Mao, Cheng-Yi Song, Guanbin Wang, Dong Westover, Kenneth D. Xu, Cheng-Xiong J Exp Clin Cancer Res Research BACKGROUND: Metastasis is a major challenge in cervical cancer treatment. Previous studies have shown that the dual functional protein apurinic/apyrimidinic endonuclease 1 (APE1) promotes tumor metastasis and is overexpressed in cervical cancer. However, the biological role and mechanism of APE1 in cervical cancer metastasis have rarely been studied. METHODS: We used gene set enrichment analysis (GSEA) to determine the APE1-related signaling pathways in cervical cancer. To investigate the role and mechanism of APE1 in cervical cancer metastasis and invasion, immunohistochemistry, immunofluorescence, western blotting, secondary structure prediction, coimmunoprecipitation, luciferase reporter, and electrophoretic mobility shift assays were performed. The inhibitory effects of the APE1 redox function inhibitor APX3330 on cervical cancer metastasis were evaluated using animal models. RESULTS: Clinical data showed that high expression of APE1 was associated with lymph node metastasis in cervical cancer patients. GSEA results showed that APE1 was associated with epithelial to mesenchymal transition (EMT) in cervical cancer. Ectopic expression of APE1 promoted EMT and invasion of cervical cancer cells, whereas inhibition of APE1 suppressed EMT and invasion of cervical cancer cells in a redox function-dependent manner. Notably, APE1 redox function inhibitor APX3330 treatment dramatically suppressed cervical cancer cell lymph node and distant metastasis in vivo. Furthermore, we found that APE1 enhanced the interaction between ZEB1 and the E-cadherin promoter by binding to ZEB1, thereby suppressing the expression of E-cadherin, a negative regulator of EMT. CONCLUSION: Our findings help to elucidate the role played by APE1 in cervical cancer metastasis and targeting APE1 redox function may be a novel strategy for inhibiting cervical cancer metastasis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-02006-5. BioMed Central 2021-07-01 /pmc/articles/PMC8246661/ /pubmed/34210327 http://dx.doi.org/10.1186/s13046-021-02006-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Li, Qing Zhou, Zhi-Wei Duan, Wei Qian, Cheng-Yuan Wang, Shu-Nan Deng, Meng-Sheng Zi, Dan Wang, Jian-Min Mao, Cheng-Yi Song, Guanbin Wang, Dong Westover, Kenneth D. Xu, Cheng-Xiong Inhibiting the redox function of APE1 suppresses cervical cancer metastasis via disengagement of ZEB1 from E-cadherin in EMT |
title | Inhibiting the redox function of APE1 suppresses cervical cancer metastasis via disengagement of ZEB1 from E-cadherin in EMT |
title_full | Inhibiting the redox function of APE1 suppresses cervical cancer metastasis via disengagement of ZEB1 from E-cadherin in EMT |
title_fullStr | Inhibiting the redox function of APE1 suppresses cervical cancer metastasis via disengagement of ZEB1 from E-cadherin in EMT |
title_full_unstemmed | Inhibiting the redox function of APE1 suppresses cervical cancer metastasis via disengagement of ZEB1 from E-cadherin in EMT |
title_short | Inhibiting the redox function of APE1 suppresses cervical cancer metastasis via disengagement of ZEB1 from E-cadherin in EMT |
title_sort | inhibiting the redox function of ape1 suppresses cervical cancer metastasis via disengagement of zeb1 from e-cadherin in emt |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246661/ https://www.ncbi.nlm.nih.gov/pubmed/34210327 http://dx.doi.org/10.1186/s13046-021-02006-5 |
work_keys_str_mv | AT liqing inhibitingtheredoxfunctionofape1suppressescervicalcancermetastasisviadisengagementofzeb1fromecadherininemt AT zhouzhiwei inhibitingtheredoxfunctionofape1suppressescervicalcancermetastasisviadisengagementofzeb1fromecadherininemt AT duanwei inhibitingtheredoxfunctionofape1suppressescervicalcancermetastasisviadisengagementofzeb1fromecadherininemt AT qianchengyuan inhibitingtheredoxfunctionofape1suppressescervicalcancermetastasisviadisengagementofzeb1fromecadherininemt AT wangshunan inhibitingtheredoxfunctionofape1suppressescervicalcancermetastasisviadisengagementofzeb1fromecadherininemt AT dengmengsheng inhibitingtheredoxfunctionofape1suppressescervicalcancermetastasisviadisengagementofzeb1fromecadherininemt AT zidan inhibitingtheredoxfunctionofape1suppressescervicalcancermetastasisviadisengagementofzeb1fromecadherininemt AT wangjianmin inhibitingtheredoxfunctionofape1suppressescervicalcancermetastasisviadisengagementofzeb1fromecadherininemt AT maochengyi inhibitingtheredoxfunctionofape1suppressescervicalcancermetastasisviadisengagementofzeb1fromecadherininemt AT songguanbin inhibitingtheredoxfunctionofape1suppressescervicalcancermetastasisviadisengagementofzeb1fromecadherininemt AT wangdong inhibitingtheredoxfunctionofape1suppressescervicalcancermetastasisviadisengagementofzeb1fromecadherininemt AT westoverkennethd inhibitingtheredoxfunctionofape1suppressescervicalcancermetastasisviadisengagementofzeb1fromecadherininemt AT xuchengxiong inhibitingtheredoxfunctionofape1suppressescervicalcancermetastasisviadisengagementofzeb1fromecadherininemt |