IL-6经TLR4/NF-κB/HIF-1α环路诱导上皮性卵巢癌恶性演进和化疗耐药的分子机制研究

Recently, a novel autocrine signaling cascade Interleukin-6(IL-6)/STAT3/hypoxia-inducible factor 1α (HIF-1α) was discovered in multiple tumor types. It has been shown that IL-6 is overexpressed in epithelial ovarian cancer (EOC) patients, and increased IL-6 concentration correlates with poor prognosis and chemoresistance. Our previous studies showed that IL-6 secreted by EOC cells may contribute to the malignant biological behavior and the refractoriness to conventional chemotherapy. However, the underlining mechanisms involved in EOC progression and chemoresistance induced by IL-6 remain unclear. In this study, clinical samples from EOC patients, IL-6-overexpressing or IL-6-deleting EOC cell models established previously and orthotopic or IL-6-deficient mouse models are used to determine whether the toll-like receptor 4(TLR4)/nuclear factor-kappaB(NF-κB)/HIF-1α loop is existed in EOC by in vitro and in vivo experiments. Further studies will investigate whether IL-6 is involved in the regulatory loop given above through a IL-6/STAT3/HIF-1α signaling cascade and thereby induces epithelial-mesenchymal transition (EMT) and malignant progression and chemoresistance in EOC. In an attempt to discover the key inflammatory factors of EMT regulatory network or molecules of related signaling pathways and to provide a new cue for estimating pathogenetic condition, judging prognois and finding the molecular targeted drug in EOC.

近年来，一个新型的自分泌信号级联IL-6/STAT3/HIF-1α在多种恶性肿瘤中被发现。IL-6在上皮性卵巢癌(EOC)中高表达，并与EOC不良预后及化疗敏感性差相关。我们前期研究发现，EOC细胞分泌的IL-6可促进其恶性生物学行为和化疗耐药，但其确切机制不清。本课题拟应用EOC患者临床标本、前期已建立的IL-6过表达或抑制表达的EOC细胞模型及EOC裸鼠皮下移植瘤和IL-6基因敲除(IL-6 KO)鼠EOC腹腔移植瘤模型，通过体外实验和体内试验首先确定EOC中是否存在TLR4/NF-κB/HIF-1α调节环路，在此基础上进一步探讨IL-6是否通过IL-6/STAT3/HIF-1α信号级联参与上述环路调节，从而诱导上皮-间质转化(EMT)发生及促进EOC恶性演进和化疗耐药。揭示EOC恶性演进过程中EMT调控网络的核心炎性因子及相关信号通路中的关键分子，将为EOC诊断及治疗提供新的靶点。

近年来，一个新型的自分泌信号级联IL-6/STAT3/HIF-1α在多种恶性肿瘤中被发现。IL-6在上皮性卵巢癌(EOC)中高表达，并与EOC不良预后及化疗敏感性差相关。我们前期研究发现，EOC细胞分泌的IL-6可促进其恶性生物学行为和化疗耐药，但其确切机制不清。本项目在原工作基础上，通过临床标本、体外实验和体内试验首先证实人EOC中存在TLR4/NF-κB/HIF-1α调节环路，在此基础上进一步证实：1）脂多糖(LPS)、低氧均可上调 EOC细胞表达IL-6，低氧可增强LPS的上述作用，而TLR4、NF-κB、HIF-1α阻断剂则抑制LPS的上述作用。2）常氧和低氧条件下，IL-6可通过激活JAK2/STAT3通路调节EOC细胞HIF-1α表达、核转位及转录活性。3）常氧和低氧条件下，IL-6可经TLR4/NF-κB/IL-6/STAT3/HIF-1α信号环路介导EOC细胞发生上皮-间质转化(EMT)。4）IL-6可经STAT3/HIF-1α信号通路抑制Let-7c和miR-200c的表达和功能，进而通过调控其相应靶基因HMGA2和ZEB1，参与诱导EMT发生及促进EOC侵袭转移和化疗耐药。本成果在国际上率先证明，人EOC中存在TLR4/NF-κB/HIF-1α调节环路，并首次证实IL-6可通过形成IL-6/STAT3/HIF-1α信号级联参与EOC细胞TLR4/NF-κB/HIF-1α环路调节，同时揭示IL-6可经STAT3/HIF-1α信号通路抑制Let-7c和miR-200c的表达和功能，进而通过调控其相应靶基因HMGA2和ZEB1，参与诱导EMT发生及促进EOC侵袭转移和化疗耐药。该成果揭示了EOC恶性演进过程中EMT调控网络的核心炎性因子及相关信号通路中的关键分子，为EOC诊断及治疗提供了新的靶点。