1. Academic Validation
  2. 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.
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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