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VAV2 is required for DNA repair and implicated in cancer radiotherapy resistance
Radiotherapy remains the mainstay for treatment of various types of human cancer; however, the clinical efficacy is often limited by radioresistance, in which the underlying mechanism is largely unknown. Here, using esophageal squamous cell carcinoma (ESCC) as a model, we demonstrate that guanine nu...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405816/ https://www.ncbi.nlm.nih.gov/pubmed/34462423 http://dx.doi.org/10.1038/s41392-021-00735-9 |
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author | Liu, Weiling Miao, Chuanwang Zhang, Shaosen Liu, Yachen Niu, Xiangjie Xi, Yiyi Guo, Wenjia Chu, Jiahui Lin, Ai Liu, Hongjin Yang, Xinyu Chen, Xinjie Zhong, Ce Ma, Yuling Wang, Yuqian Zhu, Shihao Liu, Shuning Tan, Wen Lin, Dongxin Wu, Chen |
author_facet | Liu, Weiling Miao, Chuanwang Zhang, Shaosen Liu, Yachen Niu, Xiangjie Xi, Yiyi Guo, Wenjia Chu, Jiahui Lin, Ai Liu, Hongjin Yang, Xinyu Chen, Xinjie Zhong, Ce Ma, Yuling Wang, Yuqian Zhu, Shihao Liu, Shuning Tan, Wen Lin, Dongxin Wu, Chen |
author_sort | Liu, Weiling |
collection | PubMed |
description | Radiotherapy remains the mainstay for treatment of various types of human cancer; however, the clinical efficacy is often limited by radioresistance, in which the underlying mechanism is largely unknown. Here, using esophageal squamous cell carcinoma (ESCC) as a model, we demonstrate that guanine nucleotide exchange factor 2 (VAV2), which is overexpressed in most human cancers, plays an important role in primary and secondary radioresistance. We have discovered for the first time that VAV2 is required for the Ku70/Ku80 complex formation and participates in non-homologous end joining repair of DNA damages caused by ionizing radiation. We show that VAV2 overexpression substantially upregulates signal transducer and activator of transcription 1 (STAT1) and the STAT1 inhibitor Fludarabine can significantly promote the sensitivity of radioresistant patient-derived ESCC xenografts in vivo in mice to radiotherapy. These results shed new light on the mechanism of cancer radioresistance, which may be important for improving clinical radiotherapy. |
format | Online Article Text |
id | pubmed-8405816 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-84058162021-09-16 VAV2 is required for DNA repair and implicated in cancer radiotherapy resistance Liu, Weiling Miao, Chuanwang Zhang, Shaosen Liu, Yachen Niu, Xiangjie Xi, Yiyi Guo, Wenjia Chu, Jiahui Lin, Ai Liu, Hongjin Yang, Xinyu Chen, Xinjie Zhong, Ce Ma, Yuling Wang, Yuqian Zhu, Shihao Liu, Shuning Tan, Wen Lin, Dongxin Wu, Chen Signal Transduct Target Ther Article Radiotherapy remains the mainstay for treatment of various types of human cancer; however, the clinical efficacy is often limited by radioresistance, in which the underlying mechanism is largely unknown. Here, using esophageal squamous cell carcinoma (ESCC) as a model, we demonstrate that guanine nucleotide exchange factor 2 (VAV2), which is overexpressed in most human cancers, plays an important role in primary and secondary radioresistance. We have discovered for the first time that VAV2 is required for the Ku70/Ku80 complex formation and participates in non-homologous end joining repair of DNA damages caused by ionizing radiation. We show that VAV2 overexpression substantially upregulates signal transducer and activator of transcription 1 (STAT1) and the STAT1 inhibitor Fludarabine can significantly promote the sensitivity of radioresistant patient-derived ESCC xenografts in vivo in mice to radiotherapy. These results shed new light on the mechanism of cancer radioresistance, which may be important for improving clinical radiotherapy. Nature Publishing Group UK 2021-08-30 /pmc/articles/PMC8405816/ /pubmed/34462423 http://dx.doi.org/10.1038/s41392-021-00735-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Liu, Weiling Miao, Chuanwang Zhang, Shaosen Liu, Yachen Niu, Xiangjie Xi, Yiyi Guo, Wenjia Chu, Jiahui Lin, Ai Liu, Hongjin Yang, Xinyu Chen, Xinjie Zhong, Ce Ma, Yuling Wang, Yuqian Zhu, Shihao Liu, Shuning Tan, Wen Lin, Dongxin Wu, Chen VAV2 is required for DNA repair and implicated in cancer radiotherapy resistance |
title | VAV2 is required for DNA repair and implicated in cancer radiotherapy resistance |
title_full | VAV2 is required for DNA repair and implicated in cancer radiotherapy resistance |
title_fullStr | VAV2 is required for DNA repair and implicated in cancer radiotherapy resistance |
title_full_unstemmed | VAV2 is required for DNA repair and implicated in cancer radiotherapy resistance |
title_short | VAV2 is required for DNA repair and implicated in cancer radiotherapy resistance |
title_sort | vav2 is required for dna repair and implicated in cancer radiotherapy resistance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405816/ https://www.ncbi.nlm.nih.gov/pubmed/34462423 http://dx.doi.org/10.1038/s41392-021-00735-9 |
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