Li Zongjuan, Zhang Yang, Sui Silei, Hua Yijun, Zhao Anshi, Tian Xiaoyuan, Wang Ruonan, Guo Wei, Yu Wendan, Zou Kun, Deng Wuguo, He Liru, Zou Lijuan
The Second Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Qingdao University Medical College Affiliated Yantai Yuhuangding Hospital, Yantai, China.
J Exp Clin Cancer Res. 2020 Nov 13;39(1):243. doi: 10.1186/s13046-020-01737-1.
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.
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.
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.
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.
放射治疗被视为宫颈癌治愈的一个里程碑。然而，临床结果严重受到放射抗性的阻碍。因此，探索放射抗性的潜在机制并找到潜在靶点，非常值得充分重视。
在本研究中，我们构建了两种新型的放射抗性宫颈癌细胞系，它们可以模拟临床放射抗性。为了找到新的潜在靶点，我们使用了RNA测序、数据库分析、链霉亲和素琼脂糖和液相色谱/质谱联用技术。进行了下拉实验、荧光素酶实验和拯救实验以探索调控机制。为了进一步评估治疗反应与HMGB3/hTERT表达之间的相关性，我们招募了172例宫颈癌患者。
敲低HMGB3显著抑制DNA损伤修复并诱导更多γH2AX病灶，导致体内外化疗和放射敏感性增强，而HMGB3过表达则产生相反的效果。HMGB3通过在hTERT启动子区域从-902到-321处特异性结合，转录上调hTERT，从而促进细胞生长和放射抗性。在宫颈癌细胞系和异种移植肿瘤小鼠模型中，过表达hTERT均可逆转HMGB3敲低介导的放射增敏作用。此外，来自172例宫颈癌患者的临床数据证明，HMGB3与hTERT表达呈正相关，HMGB3/hTERT高表达预示着对放疗反应不佳、TNM分期更差和生存时间更短。
在此，我们确定了HMGB3/hTERT信号轴是宫颈癌放射抗性的一个新靶点。我们的结果为宫颈癌放射抗性机制提供了新的见解，并表明靶向HMGB3/hTERT信号轴可能使宫颈癌患者受益。
