IGF-1R与Wnt协同调控β-catenin/Oct4/Sox2复合体形成维持肺癌细胞"干性"的机制

Cancer stem cells (CSCs) theory supports the concept that CSCs are critical in cancer initiation, development, recurrence and metastasis. Recently, several studies demonstrate the existence of stem-like cells in lung cancer, namely lung cancer stem cells (LCSCs), and their malignant phenotype is dependent on stemness maintenance. However, the detailed underlying mechanisms involving in the regulation of self-renewal and stemness maintenance for LCSCs are not clear. Our previous study found that both IGF-1R signaling and Wnt signaling are predominantly activated in LCSCs. Further study provided evidence that both IGF-1R and Wnt signaling play crucial roles in the regulation of self-renewal and stemness maintenance for lung CSCs. The current proposal will bring forward that IGF-1R signaling and Wnt signaling cooperatively regulate the stemness maintenance in LCSCs. We will aim to investigate the molecular mechanism of synergy effect between IGF-1R signaling and Wnt signaling on the formation of β-catenin/Oct4/Sox2 complex and transcriptional regulation of Nanog using Co-IP, GST pull-down, ChIP assay. We will also evaluate the significances of clinical diagnosis and therapeutic strategy. Our study will help the field to understand the biological characteristics and functions of LCSCs, and the discovery of LCSCs properties will have important clinical implications for diagnosis, therapy and prognosis improvement in the future, which will highlight the significance of novel and potential targets for future therapeutic approaches in cancer.

肿瘤干细胞(Cancer stem cells, CSCs)的发现为揭示肿瘤发生、发展的机制打开了新思路。近年发现肺癌细胞群体中存在干样细胞，即肺癌干细胞(LCSCs)，其恶性行为依赖于"干性"维持，但调控机制尚不清楚。申请者前期研究发现LCSCs胰岛素样生长因子-1受体(IGF-1R)与Wnt信号相伴呈高活化状态，并参与"干性"维持调控。本申请项目提出"IGF-1R与Wnt协同调控β-catenin/Oct4/Sox2复合体形成维持LCSCs干性"的科学假设，探讨上述协同信号对LCSCs自我更新及成瘤的影响，利用Co-IP、GST pull-down、ChIP等方法研究IGF-1R与Wnt协同下β-catenin/Oct4/Sox2复合体形成及调控Nanog的转录模式，并评估其临床诊断与治疗意义。研究结果对于认识LCSCs生物学特性，探索更为有效地肺癌诊疗策略和改善患者预后具有重要意义。

肿瘤干细胞(Cancer stem cells, CSCs)的发现为揭示肿瘤发生、发展的机制打开了新思路。近年发现肺癌细胞群体中存在干样细胞，即肺癌干细胞(LCSCs)，其恶性行为依赖于"干性"维持，但调控机制尚不清楚。本研究通过基因芯片技术对LCSCs和肺腺癌细胞的基因表达图谱进行分析，发现IGF-1R与Wnt信号呈高活化状态参与LCSCs自我更新的调控，且二者存在“Cross-talk”（串话）。深入研究发现，IGF-1R激活通过PI3K/AKT/GSK3β/β-catenin级联信号增强肺腺癌干样细胞POU5F1的表达，β-catenin/POU5F1/SOX2蛋白复合体激活 Nanog转录调控依赖于激活的IGF-1R/IRS-1信号。此外，对200例肺腺癌组织芯片免疫组化染色分析证实IGF-1R和干细胞表面标志物ALDH1A1的表达呈正相关且与临床预后关联，更为重要的是肺腺癌组织IGF-1R、POU5F1、β-catenin蛋白共同表达预示着肺腺癌的不良预后。该项研究阐明了依赖于IGF-1R信号的β-catenin/POU5F1/SOX2蛋白复合体维持肺癌细胞自我更新及成瘤能力的分子机制；临床联合检测IGF-1R、β-catenin、POU5F1表达对于预测肺腺癌患者的预后具有重要参考价值。研究结果对于认识LCSCs 生物学特性及机制，探索更为有效地肺癌诊疗策略和改善患者预后具有重要意义。