Chunxian Huang1, Huaiwu Lu1, Jing Li1, Xiaofei Xie1, Li Fan1, Dongyan Wang1, Wenliang Tan2, Yaxian Wang3, Zhongqiu Lin4, Tingting Yao5. 1. Department of Gynecological Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China. 2. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China. 3. Xiamen Cancer Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, People's Republic of China. 4. Department of Gynecological Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China. Electronic address: lin-zhongqiu@163.com. 5. Department of Gynecological Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China. Electronic address: yaotting@mail.sysu.edu.cn.
Abstract
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.
OBJECTIVE: Resistance to radiotherapy accounts for most treatment failures in cervical cancerpatients 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.