Dax1与Nanog协同调控肺癌干细胞发生和自我更新的分子机制

Understanding the mechanisms governing the initiation and self-renewal of lung cancer stem cells (LCSC) is an important step to overcome the drug-resistance, metastasis and recurrence of lung cancer, given the high incidence and mortality of this disease. Our previous work has demonstrated that Dax1 and Nanog, two major components of the core pluripotency network for embryonic stem cells (ESCs), cooperate to regulate ESC self-renewal and maturation of induced pluripotent stem cells (iPSCs). Recently, we observed the co-expression of these two factors in LCSC, as well as a synergistic effect on tumor initiation and self-renewal. However, the molecular mechanisms underlying are unknown. For this purpose, we plan to systematically explore the combined functions and mechanisms of Dax1 and Nanog in LCSC self-renewal and lung epithelial cell reprogramming. Moreover, through functional genomics approaches, our project aim to screen and identify novel stemness-associated genes or specific cell surface markers in LCSCs. These studies are expected to not only provide new insights into LCSC biology, but also facilitate the development of appropriate strategies for clinical diagnosis and treatment of lung cancer.

肺癌干细胞（LCSC）是导致肺癌高发病率和死亡率的根本原因。了解LCSC发生及自我更新机制是控制肺癌耐药性、转移及复发的关键。Dax1和Nanog均为胚胎干细胞（ESC）多能性核心分子。本课题组前期曾证明二者协同调节ESC自我更新及iPSCs（induced pluripotent stem cells）成熟。最近，我们发现Dax1和Nanog在LCSC内共表达，并且对LCSC自我更新和发生有明确的协同调控功能，但相关的分子机制还不清楚。本课题拟利用LCSC模型及肺上皮细胞重编程模型，通过建立Dax1/Nanog双干扰或共表达体系，探讨Dax1和Nanog协同调控LCSC发生及自我更新的分子机制；并通过功能基因组学分析，筛选和鉴定新的LCSC干性基因或特异性标志物。该研究不仅是了解LCSC生物学特性的基础，还将为肺癌的临床诊断和治疗提供新思路和理论依据。

肺癌干细胞（Lung cancer stem cell, LCSC）被认为是导致肺癌耐药性、转移及复发的关键，对LCSC的发生及自我更新机制的研究是建立靶向LCSC治疗方法的基础。Dax1和Nanog均为胚胎干细胞（ESC）多能性核心分子且功能相似，两者可协同调节ESC自我更新及iPSCs（induced pluripotent stem cells）成熟。我们前期研究发现Dax1和Nanog在LCSC内共表达并可能参与对LCSC多能性的调控。本课题旨在探讨Dax1和Nanog协同调控LCSC发生及自我更新的功能及分子机制。我们的研究结果显示：Dax1和Nanog是LCSC自我更新维持的必要条件，Dax1和/或Nanog的缺失均会导致肿瘤致瘤性降低，其机制主要为直接抑制Gata6转录并阻断其介导的分化；而过表达Dax1和Nanog则可使正常细胞发生致瘤性转化进而产生LCSC。此外，本项目还取得以下研究进展：1、Dax1存在多种剪接类型，在不同组织中特异性表达。该分子的两种剪接体Dax1F和Dax1A均参与了肺癌发生及LCSC的干性维持，且具有不同功能及调控机制，有望成为新的LCSC标志物；2、Nac1通过直接调控（促进）c-Myc基因转录，增强ESCs自我更新效率，延迟分化发生（该研究已作为论著在Oncotarget杂志发表）；3、构建了Dax1的蛋白互作网络体系（该研究已作为论著在International Journal of Biological Macromolecules杂志发表）。本研究不仅是了解LCSC生物学特性的基础，还将为肺癌的临床诊断和治疗提供新思路。