JAK2/STAT3抑制剂通过调控食管癌细胞干性促进放疗敏感性机制研究

局部晚期食管癌患者放化疗抵抗仍然是临床治疗面临的一个挑战，研究表明肿瘤干细胞与肿瘤复发转移及放化疗抵抗密切相关,然而肿瘤干细胞通过何种机制介导食管癌放疗抵抗尚不清楚。我们前期利用微球体形成与致瘤实验发现食管癌耐放射细胞干性显著增强，提示食管癌放疗抵抗可能与细胞干性相关；借助高通量筛选干细胞化合物库，我们发现4个化合物，其中JAK2/STAT3抑制剂cucurbitacin I可以抑制食管癌细胞干性。本课题探讨食管癌干细胞与放疗抵抗相关性，确定JAK2/STAT3与食管癌放疗疗效及预后的相关性；确定cucurbitacin I是否可以逆转食管癌耐放射细胞干性，与放疗联合是否可以增敏；利用食管癌PDX模型评价疗效与毒副作用；借助RNA-Seq与iTRAQ/TMT方法确定关键信号通路的改变，深入阐述cucurbitacin I通过调控食管癌细胞干性促进放疗敏感性机制，为临床治疗开辟新模式和策略。

Radiotherapy and chemotherapy resistance in patients with locally advanced esophageal cancer remains a challenge for clinical treatment. Previous studies shown that cancer stem cells are closely related to tumor recurrence, metastasis and radiochemotherapy resistance. However, mechanism of the esophageal cancer stem cells mediate radioresistance is unclear. We found that the stemness of esophageal cancer radioresistant cells was significantly enhanced compared with the parental cells using microsphere formation and tumorigenesis, suggesting that radioresistance may be related to cell stemness. Thus, we screened stem cell signaling compound library by a high-throughput way, and found 4 compounds. Among of them, JAK2/STAT3 inhibitor cucurbitacin I can inhibit the stemness of esophageal cancer cells. In this study, we explore the correlation between esophageal cancer stem cells and radioresistance, and determine that JAK2/STAT3 is involved in radioresistant, and correlated with response of radiotherapy and prognosis in esophageal cancer. Simultaneously, we definite whether cucurbitacin I can attenuate the stemness of radioresistant cells. To further evaluate the efficacy of cucurbitacin I combined with radiotherapy, we used esophageal cancer PDX models. Furthermore, we investigate the key signaling pathways or genes by RNA-Seq and iTRAQ/TMT methods, and elaborate the mechanism of cucurbitacin I promoted radiosensitivity by regulating the stemness of esophageal cancer cells. This study focus on JAK2/STAT3 inhibitor cucurbitacin I combined with radiotherapy in esophageal cancer, and open up new models and strategies for clinical esophageal cancer treatment.