cPLA2α通过DKK1/Wnt信号通路介导肿瘤干细胞的休眠与激活影响宫颈癌化疗耐药的机制研究

休眠作为肿瘤干细胞的关键特征，是造成肿瘤化疗耐药及复发转移的根源。近年研究发现，肿瘤干细胞能够在休眠及增殖活跃状态之间调节转化以适应新的环境，然而控制其状态的关键分子及信号网络仍不清楚。申请人前期研究发现宫颈癌中存在cPLA2a表达水平不同的肿瘤干细胞亚群，而cPLA2a下调的肿瘤干细胞亚群处于相对休眠状态，且呈现出较高程度的化疗耐药表型。转录组芯片及通路富集分析提示，cPLA2a下调的休眠肿瘤干细胞中DKK1/Wnt信号通路受到明显抑制。上调DKK1可使cPLA2a过表达的宫颈癌干细胞从增殖活跃状态重新进入休眠状态。据此我们推测，cPLA2a下调的肿瘤干细胞可能通过抑制DKK1/Wnt信号通路进入休眠逃避化疗杀伤。本研究拟通过一系列体外、体内实验及临床组织药敏模型，从分子、细胞、动物及临床肿瘤标本等不同层次展开研究，以期阐明cPLA2a介导肿瘤干细胞休眠与激活影响化疗耐药的分子机理。

Dormancy, a key feature of cancer stem cells (CSCs), is the major cause of chemotherapy resistance and tumor recurrence. Recent studies have revealed that CSCs regulate the transition between dormancy and proliferation to adapt to new environment. However, the mechanisms that determine the state of CSCs are unknown. Our previous study revealed that CSCs existed in two biologically distinct phenotypes characterized by different levels of cPLA2α Expression. The cPLA2α down-regulated CSC subpopulations can enter in a relatively dormant state and show strongly chemo-resistant phenotype. Transcriptome microarray analysis suggested that the DKK1/Wnt signaling pathway was significantly inhibited in cPLA2α downregulated dormant CSCs. Upregulation of DKK1 can rescue cPLA2a overexpressing CSCs from proliferation to dormanvcy. Accordingly, we hypothesized that cPLA2α down-regulated CSCs may evade attack of chemotherapy drugs by inhibiting DKK1/Wnt signaling pathway. In this study, we will investigate at the molecular, cellular, animal and clinical levels through a series of experiments in vitro and in vivo and 3D drug sensitivity models. We will make a vertical breakthrough to elucidate the molecular mechanism of cPLA2α-mediated CSCs dormancy to affect chemo-resistance。