Chemokine-Gli2信号环路调控肝癌生长的分子机制及其靶点价值

Cancer-associated fibroblasts (CAFs) is one of the most crucial components of the tumor microenvironment. Previous studies showed that CAFs promotes cancer cell growth by secreting Chemokines. However, the mechanisms whereby Chemokines promote tumor progression are only partially known. In our preliminary studies, we found that the expression of HCC-associated Chemokine genes significantly enriched in HCC tissues expressing high level Gli2. And, Chemokines (CXCL12 and CCL2) can induce expression of Gli2 in HepG2 cells in vitro. The results of bioinformatics analysis suggested that Chemokines may regulate the expression of Gli2 thought a non-classical pathway(JAK/STAT signaling pathway). Furthermore, Overexpression of Gli2 resulted in increased expression of TGFB1 gene, and transforming growth factor-β (TGF-β) has been shown to implicate in activation of CAFs. These findings indicated that TGF-β may play as a positive feedback signaling sent by Gli2 for CAFs. And, a signaling loop, based on Chemokine-Gli2, may implicate in tumor growth regulation. In this study, we will utilize several approaches including clinical cohont, cellular and molecular biology and transgenic animal model to investigate the molecular mechanisms underlying how the chemokines regulate Gli2 expression and research the regulation mechanism and target value of Chemokine-Gli2 signaling loop in HCC and CAFs. These findings will provide a new theoretical basis for HCC therapy.

在肿瘤微环境中，肿瘤相关成纤维细胞（CAFs）可通过分泌趋化因子（Chemokines）作用于癌细胞促进肿瘤生长。但趋化因子调控肿瘤生长和转移的分子机制还不完全清楚。我们的前期研究发现：在转录因子Gli2高表达的肝癌组织中趋化因子相关基因的表达显著富集，且趋化因子CXCL12及CCL2刺激后能增加HepG2细胞中Gli2的表达。生物信息学分析提示趋化因子可能通过JAK/STAT通路调控Gli2的表达。另外，过表达Gli2后肝癌细胞中TGFB1基因的表达显著上调，而TGFβ是CAFs的活化因子。提示一条潜在的以Chemokine-Gli2为关键节点的信号环路可能参与调控肿瘤生长。本研究将从临床队列、细胞、分子、动物等多个层面重点阐明趋化因子调控Gli2的分子机制，并明确Chemokine-Gli2信号环路在调控肝癌细胞与CAFs相互作用过程中的地位及靶点价值，为肝癌治疗提供新的理论依据。

在肿瘤微环境中，肿瘤相关成纤维细胞（CAFs）和巨噬细胞（TAMs）可通过分泌细胞因子（cytokines）作用于癌细胞促进肿瘤生长。但外分泌因子调控肿瘤生长和转移的分子机制还不完全清楚。我们的研究发现：CAF共培养后促进HCC细胞上调ABCC5及ABCC10的表达导致肿瘤细胞化疗耐药，趋化因子CXCL12及CCL2在CAF的条件培养基中显著上调，并作为细胞因子信号促进HepG2、Huh7细胞中ABCC5/ABCC10的表达。生物信息学分析提示趋化因子可能通过Hedgehog-GLI2通路调控ABCC5/ABCC10的表达,后续研究进一步证实了CXCL12/CCL2可非经典激活GLI2，而GLI2可直接转录激活ABCC5及ABCC10的表达进而导致肿瘤耐药。研究从临床队列、细胞、分子、动物等多个层面重点阐明趋化因子CCL2/CXCL12调控GLI2-ABCC5/ABCC10信号导致肿瘤化疗耐受的分子机制。研究另外的一项主要发现是关于肿瘤相关巨噬细胞(TAMs)通过释放TGF-β激活肿瘤细胞中GLI2及其下游IGF-II/ERK1/2信号通路促进肝癌Huh7细胞的侵袭和迁移能力。我们的研究证实了GLI2是肿瘤微环境组分（CAFs,TAMs）通过外分泌信号与肿瘤细胞相互作用的重要效应激活因子。扩展了GLI2在肝癌靶向治疗领域的新价值，为肝癌治疗提供新的理论依据。