SOX2 regulates radioresistance in cervical cancer via the hedgehog signaling pathway
SOX2 regulates radioresistance in cervical cancer via the hedgehog signaling pathway
复制标题
SOX2 通过刺猬信号通路调节宫颈癌的放射抗性。
DOI：
10.1016/j.ygyno.2018.10.005
复制
发表时间：
2018-12-01
影响因子：
4.7
通讯作者：
Yao, Tingting
中科院分区：
文献类型：
--
作者：
Huang, Chunxian;Lu, Huaiwu;Yao, Tingting
Objective.对放射治疗的抵抗是接受根治性放射治疗的宫颈癌患者治疗失败的主要原因。为探讨宫颈癌放射抵抗的可能机制，提高5年生存率，本研究重点探讨性别决定区Y盒2（sex-determining region Y-box 2，SOX 2）在宫颈癌放射抵抗中的作用及其与hedgehog（Hh）信号通路的相互作用。建立了获得性辐射抗性亚克隆细胞Hela-RR和Siha-RR。采用RT-qPCR、Western印迹分析、免疫组化、克隆生存试验、CCK-8试验、细胞凋亡分析、细胞周期分析和异种移植模型来探讨SOX 2表达与放射抵抗的关系，并确定SOX 2如何介导宫颈癌的放射抵抗。利用荧光素酶报告基因和ChIP-PCR技术研究SOX 2与Hh信号通路的相互作用。我们的研究表明，SOX 2的高表达是宫颈癌放射抵抗的原因。SOX 2与辐射诱导的细胞存活、增殖、凋亡和细胞周期变化密切相关。发现Hh信号通路在Hela-RR和Siha-RR中被激活，并且激活随着SOX 2表达而改变。SOX 2和Gli 1的免疫组化染色显示SOX 2与Hh通路密切相关。荧光素酶报告基因和ChIP-PCR分析表明，SOX 2通过占据HHAT启动子与Hh信号通路相互作用。SOX 2是宫颈癌放射抵抗的潜在治疗靶点。它通过Hh信号通路介导宫颈癌的放射抗性。(C)2018爱思唯尔公司All rights reserved.
Objective. Resistance to radiotherapy accounts for most treatment failures in cervical cancer patients who receive radical radiation therapy. To discover the possible mechanism of radioresistance and improve the 5-year survival rate, we focused on how sex-determining region Y-box 2 (SOX2) mediates radioresistance in cervical cancer as well as on the interaction between SOX2 and the hedgehog (Hh) signaling pathway in this study.Methods. We established the acquired radioresistant subclone cells Hela-RR and Siha-RR. RT-qPCR, Western blot analysis, IHC, clonogenic survival assay, CCK-8 assay, apoptosis analysis, cell cycle analysis and xenograft models were used to explore the relationship between SOX2 expression and radiation resistance and to determine how SOX2 mediates radioresistance in cervical cancer. Furthermore, luciferase reporter and ChIP-PCR assays were utilized to assess the interaction between SOX2 and the Hh signaling pathway.Results. Our research suggested that high expression of SOX2 was responsible for radioresistance in cervical cancer. SOX2 was observed to be closely related to irradiation-induced survival, proliferation, apoptosis, and cell cycle changes. The Hh signaling pathway was found to be activated in Hela-RR and Siha-RR, and the activation changed with SOX2 expression. IHC staining of SOX2 and Gli1 showed a close relationship between SOX2 and the Hh pathway. Luciferase reporter and ChIP-PCR assays demonstrated that SOX2 interacted with the Hh signaling pathway by occupying the HHAT promoter.Conclusions. SOX2 is a potential therapeutic target of irradiation resistance in cervical cancer. It mediates radioresistance in cervical cancer via the Hh signaling pathway. (C) 2018 Elsevier Inc. All rights reserved.