发育转录因子IRF6诱导鼻咽癌干样细胞分化的分子调控机制

Nasopharyngeal carcinoma (NPC) is well known as one of the most common malignancies in southern China and Southeast Asia.Almost are undifferentiated or poorly differentiated carcinoma, whichis an ideal model for induced differentiation therapy. Cancer stem cells has established itsbasis ofdevelopment, progression, recurrence and resistance treatmentin cell biological, the most prominent feature of cancer stem cell are continuous self-renewal and differentiation potential,while induced differentiation of cancer stem cells and suppress its self-renewal is a essential scientific question for target CSCs therapy. Using our previously established cellular models,genomic expression profiling revealed that interferon regulatory factor 6 (IRF6) has the significant suppressor gene’s function, as a transcriptional factor, it can significantly decrease the number of side population of CSCs in NPC, and suppress capacity of self-renewal and largely decrease tumor initiated ability, we hypothesized that IRF6 can induce CSCs differentiation and reduce its self-renewal ability. However, the mechanisms of IRF6 remain poorly understood, especially target gene haven’t been clarified clearly. Our project have performed ChIP-sep and luciferase eassy to identified regulate molecular mechanism and screen IRF6’s target gene which is related with differentiation, and try to clarify the significance of developing transcription factor IRF6 both in regulation CSCs and NPC development and progression,whichlay a essential theoretical foundation for targeted nasopharyngeal carcinoma stem cell differentiation in the treatment of translational medicine.

鼻咽癌高发于华南及东南亚地区，几乎都为未分化或低分化癌，是诱导分化治疗的理想模型，肿瘤干细胞奠定了其发生发展及治疗抗性复发转移的细胞生物学基础，其核心特点是自我更新及分化潜能，诱导其分化并抑制其自我更新是靶向干细胞治疗的关键科学问题。我们原创建立了高转移并具有干细胞样的单克隆细胞株，应用高通量芯片筛选出发育转录基因IRF6具有极强的肿瘤抑制基因功能，特别是可以显著降低鼻咽癌干细胞富集的侧群细胞SP数量，并抑制自我更新及大幅降低肿瘤启动能力，我们推测IRF6可以诱导干样细胞分化并降低其自我更新能力，但是其转录调控分子机制不明，特别是靶基因没有明确鉴定。本项目拟应用Chip-Seq及其他转录因子靶基因鉴定技术，利用体内外分化模型进一步筛选鉴定IRF6与分化相关的靶基因及其调控分子机制，阐明IRF6在肿瘤干细胞的调控作用及对鼻咽癌发生发展意义，为靶向鼻咽癌干细胞诱导分化治疗转化医学奠定理论基础。

鼻咽癌高发于华南及东南亚地区，几乎都为未分化或低分化癌，是诱导分化治疗的理想模型，肿瘤干细胞奠定了其发生发展及治疗抗性复发转移的细胞生物学基础，其核心特点是自我更新及分化潜能，诱导其分化并抑制其自我更新是靶向干细胞治疗的关键科学问题。我们原创建立了高转移并具有干细胞样的单克隆细胞株，应用高通量芯片筛选出发育转录基因IRF6具有极强的肿瘤抑制基因功能，特别是可以显著降低鼻咽癌干细胞富集的侧群细胞SP数量，并抑制自我更新及大幅降低肿瘤启动能力，我们推测IRF6可以诱导干样细胞分化并降低其自我更新能力，但是其转录调控分子机制不明，特别是靶基因没有明确鉴定。本项目拟应用Chip-Seq及其他转录因子靶基因鉴定技术，利用体内外分化模型进一步筛选鉴定IRF6与分化相关的靶基因及其调控分子机制，阐明IRF6在肿瘤干细胞的调控作用及对鼻咽癌发生发展意义，为靶向鼻咽癌干细胞诱导分化治疗转化医学奠定理论基础。