Interleukin-17A educated hepatic stellate cells promote hepatocellular carcinoma occurrence through fibroblast activation protein expression

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine Pub Date : 2024-06-11 DOI:10.1002/jgm.3693

Jun-Sheng Ni, Si-Yuan Fu, Zong-Yan Wang, Wen-Bin Ding, Jian Huang, Xing-Gang Guo, Fang-Ming Gu

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引用次数: 0

Abstract

Background

Liver cancer is typified by a complex inflammatory tumor microenvironment, where an array of cytokines and stromal cells orchestrate a milieu that significantly influences tumorigenesis. Interleukin-17A (IL-17A), a pivotal pro-inflammatory cytokine predominantly secreted by Th17 cells, is known to play a substantial role in the etiology and progression of liver cancer. However, the precise mechanism by which IL-17A engages with hepatic stellate cells (HSCs) to facilitate the development of hepatocellular carcinoma (HCC) remains to be fully elucidated. This investigation seeks to unravel the interplay between IL-17A and HSCs in the context of HCC.

Methods

An HCC model was established in male Sprague–Dawley rats using diethylnitrosamine to explore the roles of IL-17A and HSCs in HCC pathogenesis. In vivo overexpression of Il17a was achieved using adeno-associated virus. A suite of molecular techniques, including RT-qPCR, enzyme-linked immunosorbent assays, Western blotting, cell counting kit-8 assays and colony formation assays, was employed for in vitro analyses.

Results

The study findings indicate that IL-17A is a key mediator in HCC promotion, primarily through the activation of hepatic progenitor cells (HPCs). This pro-tumorigenic influence appears to be mediated by HSCs, rather than through a direct effect on HPCs. Notably, IL-17A-induced expression of fibroblast activation protein (FAP) in HSCs emerged as a critical factor in HCC progression. Silencing Fap in IL-17A-stimulated HSCs was observed to reverse the HCC-promoting effects of HSCs.

Conclusions

The collective evidence from this study implicates the IL-17A/FAP signaling axis within HSCs as a contributor to HCC development by enhancing HPC activation. These findings bolster the potential of IL-17A as a diagnostic and preventative target for HCC, offering new avenues for therapeutic intervention.

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白细胞介素-17A教育的肝星状细胞通过成纤维细胞活化蛋白的表达促进肝细胞癌的发生。

背景：肝癌的典型特征是具有复杂的炎症性肿瘤微环境，在这种环境中，一系列细胞因子和基质细胞组成了一个环境，对肿瘤发生产生了重大影响。白细胞介素-17A（IL-17A）是一种主要由 Th17 细胞分泌的关键性促炎细胞因子，在肝癌的病因和进展中发挥着重要作用。然而，IL-17A 与肝星状细胞（HSCs）相互作用促进肝细胞癌（HCC）发展的确切机制仍有待全面阐明。本研究试图揭示IL-17A与造血干细胞在HCC中的相互作用：方法：用二乙基亚硝胺在雄性 Sprague-Dawley 大鼠体内建立了一个 HCC 模型，以探讨 IL-17A 和造血干细胞在 HCC 发病机制中的作用。利用腺相关病毒实现了Il17a的体内过表达。体外分析采用了一系列分子技术，包括 RT-qPCR、酶联免疫吸附试验、Western 印迹、细胞计数试剂盒-8 试验和集落形成试验：研究结果表明，IL-17A 是促进 HCC 的关键介质，主要是通过激活肝祖细胞（HPCs）。这种促肿瘤作用似乎是由造血干细胞介导的，而不是通过直接作用于 HPCs。值得注意的是，IL-17A 诱导的成纤维细胞活化蛋白（FAP）在造血干细胞中的表达成为 HCC 进展的关键因素。据观察，抑制 IL-17A 刺激的造血干细胞中的 FAP 可逆转造血干细胞对 HCC 的促进作用：本研究的综合证据表明，造血干细胞中的 IL-17A/FAP 信号轴通过增强造血干细胞的活化作用而促进了 HCC 的发展。这些发现增强了 IL-17A 作为 HCC 诊断和预防靶点的潜力，为治疗干预提供了新途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Gene Medicine 医学-生物工程与应用微生物

CiteScore

6.40

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： The aims and scope of The Journal of Gene Medicine include cutting-edge science of gene transfer and its applications in gene and cell therapy, genome editing with precision nucleases, epigenetic modifications of host genome by small molecules, siRNA, microRNA and other noncoding RNAs as therapeutic gene-modulating agents or targets, biomarkers for precision medicine, and gene-based prognostic/diagnostic studies. Key areas of interest are the design of novel synthetic and viral vectors, novel therapeutic nucleic acids such as mRNA, modified microRNAs and siRNAs, antagomirs, aptamers, antisense and exon-skipping agents, refined genome editing tools using nucleic acid /protein combinations, physically or biologically targeted delivery and gene modulation, ex vivo or in vivo pharmacological studies including animal models, and human clinical trials. Papers presenting research into the mechanisms underlying transfer and action of gene medicines, the application of the new technologies for stem cell modification or nucleic acid based vaccines, the identification of new genetic or epigenetic variations as biomarkers to direct precision medicine, and the preclinical/clinical development of gene/expression signatures indicative of diagnosis or predictive of prognosis are also encouraged.