Hypoxia-induced downregulation of B-cell translocation gene 3 confers resistance to radiation therapy of colorectal canc
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ORIGINAL ARTICLE – CANCER RESEARCH
Hypoxia‑induced downregulation of B‑cell translocation gene 3 confers resistance to radiation therapy of colorectal cancer Dening Ma1,3 · Xinyi Gao2,3 · Jinhua Tao1,3 · Hongming Yu4 · Zongtao Chai4 Received: 17 May 2020 / Accepted: 27 June 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Background Colorectal cancer (CRC) is now a major human cancer, and B-cell translocation gene 3 (BTG3) has been reported as a tumor-suppressor in CRC, but its upstream regulator has not been identified. Methods Endogenous expression levels of BTG3 were compared between normal colorectal cell line CCD-18Co and two CRC cell lines SW480 and HT29, as well as between CRC patient tumor and adjacent normal tissues. Analysis of BTG3 genomic region was performed which identified a putative hypoxia response element (HRE). Effects of hypoxia condition, BTG3 overexpression, and their combination on the radiation sensitivity of CRC cell lines were assessed. Results BTG3 was downregulated in CRC cell lines and patient tumor samples, via the HRE in its promoter region. Hypoxia and BTG3 overexpression could both induce radiation resistance in CRC cells. Combining hypoxia with BTG3 overexpression effectively rendered the resistance of CRC cells to radiation to a level lower than hypoxia alone and higher than normoxia alone, indicating the essential role of BTG3 in hypoxia-induced radiation resistance of CRC cells. Conclusion We therefore propose a novel signaling cascade involving hypoxia/BTG3 to be a potential risk factor for CRC patients undergoing radiation therapy, which could possibly serve as therapeutic targets among CRC patients with acquired radiotherapy resistance. Keywords Colorectal cancer · B-cell translocation gene 3 · Hypoxia · Radiation therapy · Resistance
Introduction Dening Ma and Xinyi Gao have contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00432-020-03307-6) contains supplementary material, which is available to authorized users. * Zongtao Chai [email protected] 1
Department of Colorectal Surgery, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), 1 Banshan East Road, Hangzhou 310022, Zhejiang, China
2
Department of Radiology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), 1 Banshan East Road, Hangzhou 310022, Zhejiang, China
3
Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, 1 Banshan East Road, Hangzhou 310022, China
4
Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China
Colorectal cancer (CRC) is now a major type of human cancer among western populations, which accounts for ~ 10% of death associated with cancer (Kuipers et al. 2015). The increasing CRC incidences could be attributed to the life styles with inadequate physical activities, habit of smoking and poor
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