Targeting HMGB3/hTERT axis for radioresistance in cervical cancer
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(2020) 39:243
RESEARCH
Open Access
Targeting HMGB3/hTERT axis for radioresistance in cervical cancer Zongjuan Li1†, Yang Zhang2†, Silei Sui1†, Yijun Hua3, Anshi Zhao3, Xiaoyuan Tian1, Ruonan Wang1, Wei Guo1, Wendan Yu1, Kun Zou4, Wuguo Deng3*, Liru He3* and Lijuan Zou1*
Abstract Background: Radiotherapy is regarded as a milestone for the cure of cervical cancer. However, clinical outcome heavily be hindered by radioresistance. So, exploring the underlying mechanism of radioresistance, and find potential target, well deserve fully emphasis. Methods: In this study, we developed two novel radiation resistance cervical cancer cell lines, which could mimic clinical radioresistance. In order to find new potential targets, RNA-Seq, database analysis, streptavidin-agarose and LC/MS were used. Pull-down, luciferase and rescue assays were conducted to explore the regulatory mechanisms. To further evaluate the correlation between therapeutic responses and HMGB3/hTERT expression, 172 cervical cancer patients were recruited. Results: Knockdown of HMGB3 significantly inhibit the DNA damage repair and induced more γH2AX foci, leading to enhanced chemo- and radio-sensitivity in vitro and in vivo, whereas HMGB3 overexpression has the opposite effects. HMGB3 promotes cell growth and radioresistance by transcriptionally up-regulating hTERT via the specifical binding of HMGB3 at the hTERT promoter region from − 902 to − 321. HMGB3 knockdown-mediated radiosensitization could be reversed by the overexpressed hTERT in both cervical cancer cell lines and xenograft tumor mouse model. Furthermore, clinical data from 172 cervical cancer patients proved that there was a positive correlation between HMGB3 and hTERT expression, and high expression of HMGB3/hTERT predicted poor response to radiotherapy, worse TNM stages and shorter survival time. Conclusion: Here, we have identified HMGB3/hTERT signaling axis as a new target for cervical cancer radioresistance. Our results provide new insights into the mechanism of cervical cancer radioresistance and indicate that targeting the HMGB3/hTERT signaling axis may benefit cervical cancer patients. Keywords: Cervical cancer, HMGB3, hTERT, Radioresistance
* Correspondence: [email protected]; [email protected]; [email protected] † Zongjuan Li, Yang Zhang and Silei Sui contributed equally to this work. 3 SunYat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China 1 The Second Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China Full list of author information is available at the end of the article © The Author(s). 2020 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 licence, and indicate if chan
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