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刺猬信号通路通过CCL20-CCR6轴促进单核细胞浸润于肝细胞癌中。

The Hedgehog Pathway Promotes Monocytes Infiltration Through CCL20-CCR6 Axis in Hepatocellular Carcinoma.

作者信息

Chu Pei-Han, Hsu Yu-Fu, Chang Chen-Yi, Leu Chuen-Miin, Chen Kuo-Hsin, Chang Chiung-Fang, Tseng Ping-Hui

机构信息

School of Life Science, Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan.

School of Life Science, Institute of Microbiology and Immunology, National Yang Ming Chiao Tung University, Taipei, Taiwan.

出版信息

J Cell Mol Med. 2025 Sep;29(17):e70824. doi: 10.1111/jcmm.70824.


DOI:10.1111/jcmm.70824
PMID:40913253
Abstract

Hepatocellular carcinoma (HCC) is one of the leading cancers worldwide, and its development is strongly associated with the tumour microenvironment, particularly fibrosis and chronic inflammation. This study aims to investigate the role of the Hedgehog (Hh) pathway, a key signalling pathway in HCC progression, in the interaction between HCC cells and monocytes, which are central players in inflammation. Using a transwell migration assay, GLI1, the downstream transcriptional effector of the Hh pathway in HCC cells, was found to promote the migration of THP-1 monocyte cells. Among the cytokines regulated by the Hh pathway in HCC cells, CCL20 was identified as a crucial factor that interacts with CCR6 in THP-1 cells to facilitate migration. Next, using a luciferase reporter assay and chromatin immunoprecipitation, GLI1 binding sites within the CCL20 promoter region were confirmed. In a xenograft tumour mouse model, tumour growth and monocyte infiltration were inhibited in GLI1 or CCL20 knockout PLC5 cells. Moreover, mRNA expressions of GLI1 and CCL20 were positively correlated in clinical samples, with patients exhibiting high CCL20 expression showing poorer overall survival. Overall, our findings highlight that the Hh pathway in HCC contributes to monocyte infiltration via the CCL20-CCR6 axis, providing potential insights for future therapeutic strategies.

摘要

肝细胞癌(HCC)是全球主要癌症之一,其发展与肿瘤微环境密切相关,尤其是纤维化和慢性炎症。本研究旨在探讨Hedgehog(Hh)通路在HCC进展中的关键信号通路,在HCC细胞与单核细胞(炎症中的核心参与者)相互作用中的作用。通过Transwell迁移试验,发现HCC细胞中Hh通路的下游转录效应因子GLI1可促进THP-1单核细胞的迁移。在HCC细胞中由Hh通路调节的细胞因子中,CCL20被确定为与THP-1细胞中的CCR6相互作用以促进迁移的关键因子。接下来,使用荧光素酶报告基因检测和染色质免疫沉淀,证实了CCL20启动子区域内的GLI1结合位点。在异种移植肿瘤小鼠模型中,GLI1或CCL20基因敲除的PLC5细胞中肿瘤生长和单核细胞浸润受到抑制。此外,临床样本中GLI1和CCL20的mRNA表达呈正相关,CCL20表达高的患者总生存率较差。总体而言,我们的研究结果表明,HCC中的Hh通路通过CCL20-CCR6轴促进单核细胞浸润,为未来的治疗策略提供了潜在的见解。

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The Hedgehog Pathway Promotes Monocytes Infiltration Through CCL20-CCR6 Axis in Hepatocellular Carcinoma.

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