Targeting HMGB3/hTERT axis for radioresistance in cervical cancer.
Targeting HMGB3/hTERT axis for radioresistance in cervical cancer.
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针对宫颈癌放射抗性的 HMGB3/hTERT 轴。
DOI：
10.1186/s13046-020-01737-1
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发表时间：
2020-11-13
期刊：
影响因子：
--
通讯作者：
Zou L
中科院分区：
文献类型：
--
作者：
Li Z;Zhang Y;Sui S;Hua Y;Zhao A;Tian X;Wang R;Guo W;Yu W;Zou K;Deng W;He L;Zou L
放疗被认为是宫颈癌治疗的一个里程碑。然而，临床结果严重受到放射耐药的影响。因此，探索辐射抗性的潜在机制，寻找潜在的靶点，是值得充分重视的。在这项研究中，我们培育了两种新的放射耐药宫颈癌细胞系，可以模拟临床放射耐药。为了寻找新的潜在靶点，采用RNA-Seq、数据库分析、链亲和素琼脂糖和LC/MS等方法。通过Pull-down、荧光素酶和拯救实验探讨其调控机制。为了进一步评估治疗反应与HMGB3/hTERT表达的相关性，我们招募了172例宫颈癌患者。HMGB3的低表达显著抑制DNA损伤修复，诱导更多的γ - h2ax病灶，导致体外和体内化疗和放射敏感性增强，而HMGB3的过表达则具有相反的作用。HMGB3通过特异性结合hTERT启动子区（−902 ~−321），通过转录上调hTERT，促进细胞生长和抗辐射。HMGB3敲低介导的放射致敏可被过表达的hTERT在宫颈癌细胞系和异种移植瘤小鼠模型中逆转。172例宫颈癌患者的临床资料证实HMGB3与hTERT表达呈正相关，HMGB3/hTERT高表达预示放疗反应差、TNM分期差、生存时间短。本研究发现HMGB3/hTERT信号轴是宫颈癌放射耐药的新靶点。我们的研究结果为宫颈癌放射耐药机制提供了新的见解，并表明靶向HMGB3/hTERT信号轴可能有益于宫颈癌患者。本文附有补充信息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. Supplementary information accompanies this paper at 10.1186/s13046-020-01737-1.
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