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
  • 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. [email protected].
  • 6. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China. [email protected].
  • 7. Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. [email protected].
  • 8. CAMS Key Laboratory of Genetics and Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • 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. [email protected].
  • 10. Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. [email protected].
  • 11. CAMS Key Laboratory of Genetics and Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • # 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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