2. Academic Validation
  3. VAV2 is required for DNA repair and implicated in cancer radiotherapy resistance

VAV2 is required for DNA repair and implicated in cancer radiotherapy resistance

  • Signal Transduct Target Ther. 2021 Aug 30;6(1):322. doi: 10.1038/s41392-021-00735-9.
Weiling Liu  # 1,  Chuanwang Miao  # 1,  Shaosen Zhang  # 1,  Yachen Liu 1,  Xiangjie Niu 1,  Yiyi Xi 1,  Wenjia Guo 2 3,  Jiahui Chu 4,  Ai Lin 1,  Hongjin Liu 1,  Xinyu Yang 1,  Xinjie Chen 1,  Ce Zhong 1,  Yuling Ma 1,  Yuqian Wang 1,  Shihao Zhu 1,  Shuning Liu 1,  Wen Tan 1,  Dongxin Lin 5 6 7 8,  Chen Wu 9 10 11
Affiliations

Affiliations

  • 1 Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 2 Cancer Institute, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China.
  • 3 Key Laboratory of Oncology of Xinjiang Uygur Autonomous Region, Urumqi, China.
  • 4 Department of pharmacy, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 5 Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. lindx@cicams.ac.cn.
  • 6 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China. lindx@cicams.ac.cn.
  • 7 Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. lindx@cicams.ac.cn.
  • 8 CAMS Key Laboratory of Genetics and Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. lindx@cicams.ac.cn.
  • 9 Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. chenwu@cicams.ac.cn.
  • 10 Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. chenwu@cicams.ac.cn.
  • 11 CAMS Key Laboratory of Genetics and Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. chenwu@cicams.ac.cn.
  • # Contributed equally.
PMID: 34462423 DOI: 10.1038/s41392-021-00735-9
Abstract

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.

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