分割照射下，Snail介导上皮间质转化与肿瘤细胞“干性”调控鼻咽癌放疗抵抗的作用机制研究

Radioresistance induced by fractionated irradiation is the underlying cause of local recurrence and treatment failure in nasopharyngeal carcinoma (NPC). Epithelial mesenchymal transition (EMT) and cancer cell stemness were shown to participate in tumor radioresistance. However, the fundamental mechanism remains to be clarified.. Our preliminary experimental results suggested that ionizing radiation is able to promote the expression of Snail, an EMT transcription factor, in various NPC cells. What’s more, Snail could regulate cancer stemness and radiosensitivity of NPC cells. Thus, we hypothesize that Snail is the most important factor which connects EMT, cancer stemness with NPC radioresistance. Fractionated irradiation upregulates Snail which then induces EMT and cancer stemness resulting in NPC radioresistance.. NPC tissues, parental cell lines and radioresistant cell lines will be adopted as experimental subjects. Firstly, the function of EMT and cancer stemness in NPC radioresistance will be demonstrated. Secondly, the role of Snail in regulating EMT, cancer stemness and NPC radioresistance will be analyzed. Meanwhile, the relationship between Snail, EMT and cancer stemness will be clarified. Finally, RNA interference, ChIP, confocal immunofluorescence, gene microarray techniques and bioinformatics tools will be used to reveal the molecular mechanism of Snail-mediated EMT and cancer stemness in regulating NPC radioresistance. Systemic studies of our project will provide basic theory and experimental evidence for reversing NPC radioresistance.

分割照射诱发的放疗抵抗是鼻咽癌复发、以致治疗失败的内在原因。上皮间质转化(EMT)与肿瘤细胞“干性”参与放疗抵抗，但具体机制不明。我们前期研究提示：①分割照射可以上调EMT转录因子Snail的表达；②Snail可以调控肿瘤细胞“干性”与放疗敏感性。据此，我们推测：Snail是连接EMT、肿瘤细胞“干性”、放疗抵抗的关键；即分割照射下，Snail上调，介导EMT与肿瘤细胞“干性”，继而诱发放疗抵抗。本项目拟以鼻咽癌组织标本、亲本细胞系、放疗抵抗细胞系为研究对象。首先证明EMT、肿瘤细胞“干性”参与鼻咽癌放疗抵抗；随后探讨Snail对EMT、肿瘤细胞“干性”、放疗抵抗的调控作用，并阐明它们的内在关系；最后应用RNA干扰、ChIP、免疫共聚焦、基因芯片、生物信息学软件分析等技术揭示Snail介导EMT与肿瘤细胞“干性”参与放疗抵抗的确切机制。本项目将为逆转鼻咽癌放疗抵抗提供理论基础和实验依据。

分割照射诱发的放疗抵抗是鼻咽癌复发、以致治疗失败的内在原因。上皮间质转化(EMT)与肿瘤细胞“干性”参与放疗抵抗，但具体机制不明。我们前期研究提示：①分割照射可以上调EMT转录因子Snail的表达；②Snail可以调控肿瘤细胞“干性”与放疗敏感性。据此，我们推测：Snail是连接EMT、肿瘤细胞“干性”、放疗抵抗的关键；即分割照射下，Snail上调，介导EMT与肿瘤细胞“干性”，继而诱发放疗抵抗。本项目拟以鼻咽癌组织标本、亲本细胞系、放疗抵抗细胞系为研究对象。首先证明EMT、肿瘤细胞“干性”参与鼻咽癌放疗抵抗；随后探讨Snail对EMT、肿瘤细胞“干性”、放疗抵抗的调控作用，并阐明它们的内在关系；最后应用RNA干扰、ChIP、免疫共聚焦、基因芯片、生物信息学软件分析等技术揭示Snail介导EMT与肿瘤细胞“干性”参与放疗抵抗的确切机制。本项目将为逆转鼻咽癌放疗抵抗提供理论基础和实验依据。