Hes1靶向多梳基因蛋白EZH2调控鼻咽癌增殖和干性的研究

Recurrence and distant metastasis are the main reasons for the treatment failure of nasopharyngeal carcinoma (NPC). Cancer stem cells (CSCs) are characterised by unlimited cell division and treatment resistance, are the source of tumor recurrence and metastasis. Therefore, developing the effective approach for depleting NPC CSCs are crucial to improve the therapeutic effects of patients. The pre experiments we have shown that, Hes1 enhanced the proliferation of NPC cells in vitro; Overexpressing Hes1 in NPC cells upregulated the expression of stem cell related genes, and increased the numbers of SP cells and tumor spheres formation. Chromatin immunoprecipitation assay showed that Hes1 directly binded to the promoter region of EZH2. These findings suggest that Hes1 can regulate NPC stem features by directly targeting EZH2. In this study, we aim mainly to investigate the effects of Hes1 on self-renewal, apoptosis, differentiation or resistance to the radiotherapy of NPC CSCs, and to detect whether these functions are mediated by its target gene EZH2. The in vivo inhibitory effects of EZH2 alone or in combination with radiotherapy on NPC CSCs are further to be explored; the relationship between Hes1, EZH2 and NPC CSCs, and clinical pathological significance will also be clarified. This study will elucidate the role of Hes1 in regulating the proliferation and tumorigenesis of NPC, which might provide a potential treatment strategy for CSCs.

复发和远处转移是鼻咽癌治疗失败的主要原因；具有无限增殖潜能的肿瘤干细胞(CSCs)对放化疗有很强抗性，是肿瘤复发和转移根源。因此寻找有效清除鼻咽癌CSCs的治疗靶点，对提高鼻咽癌治疗效果有重要意义。我们前期研究首次发现，Hes1过表达增强NPC细胞增殖，上调干性基因表达和增加SP细胞含量和肿瘤球形成；并且，Hes1正向调控NPC细胞中EZH2的表达，提示Hes1很可能通过靶向EZH2进而调控NPC细胞的干性。本项目拟全面解析Hes1对鼻咽癌CSCs自我更新、凋亡、分化和放疗抵抗等的影响，并明确Hes1上述功能可否由下游靶基因EZH2介导，并进一步探讨EZH2抑制剂或联合放疗对CSCs体内清除效果；临床标本验证Hes1和EZH2等与鼻咽癌CSCs的关系及临床病理意义。本研究将阐明Hes1在NPC增殖和干性调控中的作用，有助于探求肿瘤干细胞靶向治疗的潜在靶点。

复发和远处转移是鼻咽癌治疗失败的主要原因；具有无限增殖潜能的肿瘤干细胞(CSCs)对 放化疗有很强抗性，是肿瘤复发和转移根源。因此寻找有效清除鼻咽癌CSCs的治疗靶点，对提高鼻咽癌治疗效果有重要意义。本项目拟全面解析Hes1对鼻咽癌CSCs自我更新、凋亡、分化等的影响，并明确Hes1上述功能可否由下游靶基因EZH2和Bmi-1介导；临床标本验证Hes1和EZH2等与鼻咽癌CSCs的关系及临床病理意义。本课题发现，鼻咽癌组织中Hes1表达与TNM分期和临床分期以及患者预后密切相关。Hes1过表达增强NPC细胞增殖，上调干性基因表达和增加SP细胞含量和肿瘤球形成；并且，转录因子Hes1靶向EZH2和Bmi-1调控NPC细胞干性维持。本研究将阐明Hes1在NPC增殖和干性调控中的作用，有助于探求肿瘤干细胞靶向治疗的潜在靶点。