YAP1/TEAD4复合体靶向CXCL5调控宫颈癌细胞放射后再增殖的机制研究

宫颈癌细胞放射后再增殖是影响其放射敏感性，导致首程治疗肿瘤退缩不良及疾病早期复发的重要因素，但目前缺乏有效生物学评价指标及分子治疗靶点。前期工作筛选TCGA数据库中接受放疗的宫颈癌患者队列，结果发现，YAP1及CXCL5在放疗后早期复发患者中表达均显著增高，与疾病不良预后有关。根据体外细胞实验及生信分析结果推测，YAP1可能与转录因子TEAD4形成复合体，促进下游靶基因CXCL5表达，继而影响放射后细胞存活及再增殖功能，但其具体调控机制尚不明确。因此，项目拟通过构建细胞、动物模型，首先明确YAP1及CXCL5对宫颈癌细胞放射后再增殖动力改变的影响；然后重点解析YAP1/TEAD4复合体形成，及其在CXCL5转录水平上的调控关系和具体作用位点；最后由临床样本验证YAP1、CXCL5在宫颈癌放疗后肿瘤退缩及复发评价中的一致性，为宫颈癌放疗后复发风险预测及个体化治疗靶点开发提供理论依据。

Cervical cancer cell re-population and re-proliferation after irradiation are known of great importance for effectively tumor control. However, there is no definite biomarker for clinician to predict radiation resistance, early recurrence，following poor prognosis or individualized treatment in advance. Here, we collected cervical cancer patient cohort from TCGA database, comparing early recurrence within 5 years after radiotherapy with those of no recurrence. The differential gene expression profiles showed that YAP1 expression was significantly increased in patients with early recurrence, resulting in poor prognosis regarding of overall survival. According to the previous exploration with YAP1 knockdown Siha cell line in vitro and following bioinformatic analysis, it is suggested that YAP1 might promote the CXCL5 expression by bind to its transcription factor TEAD4, thus facilitating cell survival and re-proliferation after irradiation. Based on this, our project aims to further elucidate the role of YAP1 in cervical cancer radiosensitivity and potential regulation mechanism between YAP1 and downstream target gene CXCL5. Firstly, we would confirm the active roles of YAP1 and CXCL5 in cervical cancer cell re-proliferation dynamics after irradiation in vitro and in vivo; then clarify transcriptional regulation and specific binding site(s) of YAP1/TEAD4 complex while targeting CXCL5 and promoting cell proliferation. Finally, verifying the role of YAP1 and CXCL5 in the irradiation reaction and prognosis prediction among cervical cancer patients using primary tumor samples. Our exploration would provide theoretical basis for the valid biomarker among cervical cancer patients receiving radiotherapy，which helps to realize timely evaluation after definite radiotherapy and precise recurrence risk prediction, optimizing individualized treatment strategy in clinical practice.