Scholarlink

<p>Exosomes derived from cancer-associated fibroblasts (CAFs) play a crucial role in cancer development. Fos-like antigen 1 (FOSL1) exhibits oncogenic properties across various malignancies. However, the specific role of FOSL1 in CAFs-derived exosomes (CAFs-EXO) in hepatocellular carcinoma (HCC) has not been previously explored. This study aimed to investigate whether CAFs-EXO transfer FOSL1 to HCC cells and to examine the functional consequences of this transfer. HCC-related CAFs and their exosomes were used to incubate HCC cells. Cell proliferation and migration/invasion were assessed. The percentage of CD11b<sup>+</sup>CD206<sup>+</sup> macrophages was measured. The FOSL1/PLAU relationship was validated by chromatin immunoprecipitation (ChIP) and luciferase assays. FOSL1 expression was increased in CAFs-EXO compared with normal controls (3.36 ± 0.25 vs. 1.00 ± 0.04, <i>P</i> &lt; 0.001). CAFs-EXO transmitted FOSL1 into HCC cells, promoting HCC cell proliferation (Huh-7 cells: 63.93 ± 2.68 vs. 54.37 ± 0.8, <i>P</i> &lt; 0.01; Hep3B: 63.27 ± 5.13 vs. 51.9 ± 1.75, <i>P</i> &lt; 0.01). CAFs-EXO enhanced cell migration (Huh-7 cells: 197.33 ± 12.06 vs. 153.0 ± 6.25, <i>P</i> &lt; 0.05; Hep3B: 215.33 ± 29.14 vs. 143.0 ± 7.55, <i>P</i> &lt; 0.01) and invasion (Huh-7 cells: 176.67 ± 19.86 vs. 130.33 ± 8.62, <i>P</i> &lt; 0.01; Hep3B: 191.0 ± 8.19 vs. 121.0 ± 7.0, <i>P</i> &lt; 0.001). CAFs-EXO increased pro-tumorigenic M2 macrophage polarization by transmitting FOSL1. Moreover, CAFs-EXO affected the in vivo growth and metastasis of HCC cells through FOSL1. Mechanistically, FOSL1 activated <i>PLAU</i> transcription. FOSL1 promoted HCC cell malignant phenotypes and pro-tumorigenic M2 macrophage polarization by upregulating PLAU. Additionally, PLAU depletion suppressed HCC malignant phenotypes and decreased pro-tumorigenic M2 macrophage polarization. This study provides the first evidence that CAFs-EXO transport FOSL1 into HCC cells, thereby influencing HCC progression through the activation of <i>PLAU</i> transcription. These findings highlight the FOSL1/PLAU axis as a previously unrecognized therapeutic target in HCC.</p> Graphical Abstract <p> In hepatocellular carcinoma (HCC), cancer-associated fibroblasts (CAFs) secrete exosomes to transmit FOSL1 into HCC cells and thus upregulate PLAU expression transcriptionally, leading to HCC cell malignant phenotypes and macrophage M2 polarization.</p> <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Exosomal FOSL1 From Cancer-associated Fibroblasts Drives the Progression and Pro-tumorigenic M2 Macrophage Polarization of Hepatocellular Carcinoma By Activating PLAU Transcription

  • 期刊论文

  • 发表日期：

    2025年11月20日

查看全文
  • Kai Bai,
  • Ruopeng Liang,
  • Jian Li,
  • Kun Zhao

摘要

Exosomes derived from cancer-associated fibroblasts (CAFs) play a crucial role in cancer development. Fos-like antigen 1 (FOSL1) exhibits oncogenic properties across various malignancies. However, the specific role of FOSL1 in CAFs-derived exosomes (CAFs-EXO) in hepatocellular carcinoma (HCC) has not been previously explored. This study aimed to investigate whether CAFs-EXO transfer FOSL1 to HCC cells and to examine the functional consequences of this transfer. HCC-related CAFs and their exosomes were used to incubate HCC cells. Cell proliferation and migration/invasion were assessed. The percentage of CD11b+CD206+ macrophages was measured. The FOSL1/PLAU relationship was validated by chromatin immunoprecipitation (ChIP) and luciferase assays. FOSL1 expression was increased in CAFs-EXO compared with normal controls (3.36 ± 0.25 vs. 1.00 ± 0.04, P < 0.001). CAFs-EXO transmitted FOSL1 into HCC cells, promoting HCC cell proliferation (Huh-7 cells: 63.93 ± 2.68 vs. 54.37 ± 0.8, P < 0.01; Hep3B: 63.27 ± 5.13 vs. 51.9 ± 1.75, P < 0.01). CAFs-EXO enhanced cell migration (Huh-7 cells: 197.33 ± 12.06 vs. 153.0 ± 6.25, P < 0.05; Hep3B: 215.33 ± 29.14 vs. 143.0 ± 7.55, P < 0.01) and invasion (Huh-7 cells: 176.67 ± 19.86 vs. 130.33 ± 8.62, P < 0.01; Hep3B: 191.0 ± 8.19 vs. 121.0 ± 7.0, P < 0.001). CAFs-EXO increased pro-tumorigenic M2 macrophage polarization by transmitting FOSL1. Moreover, CAFs-EXO affected the in vivo growth and metastasis of HCC cells through FOSL1. Mechanistically, FOSL1 activated PLAU transcription. FOSL1 promoted HCC cell malignant phenotypes and pro-tumorigenic M2 macrophage polarization by upregulating PLAU. Additionally, PLAU depletion suppressed HCC malignant phenotypes and decreased pro-tumorigenic M2 macrophage polarization. This study provides the first evidence that CAFs-EXO transport FOSL1 into HCC cells, thereby influencing HCC progression through the activation of PLAU transcription. These findings highlight the FOSL1/PLAU axis as a previously unrecognized therapeutic target in HCC.

Graphical Abstract

In hepatocellular carcinoma (HCC), cancer-associated fibroblasts (CAFs) secrete exosomes to transmit FOSL1 into HCC cells and thus upregulate PLAU expression transcriptionally, leading to HCC cell malignant phenotypes and macrophage M2 polarization.