IFN-treated macrophage-derived exosomes prevents HBV-HCC migration and invasion via regulating miR-106b-3p/PCGF3/PI3K/AKT signaling axis.

IF 4.6 2区医学 Q2 IMMUNOLOGY

Frontiers in Cellular and Infection Microbiology Pub Date : 2024-10-28 eCollection Date: 2024-01-01 DOI:10.3389/fcimb.2024.1421195

Jing Chen, Qi Yin, Shiheng Xu, Xiaoqing Tan, Yu Liang, Chaohui Chen, Li Li, Tao Zhang, Tao Shen

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Abstract

Background: Studies revealed that exosomes from IFN-α-treated liver non-parenchymal cells (IFN-exo) mediate antiviral activity. MiR-106b-3p has been shown to play a paradoxical role in disease progressing from different studies. However, its specific role in HBV-related hepatocellular carcinoma (HBV-HCC) and the underlying mechanism remains unclear.

Method: Huh7 cells transient transfected with plasmids of HBV-C2 and B3 were co-cultured with IFN-exo. Cell supernatants were collected to detect miR-106b-3p, HBsAg, HBeAg and HBV DNA levels. Cell proliferation, apoptosis, migration and invasion were analyzed. The putative targets of miR-106b-3p were identified by a dual-luciferase reporter system. The expression of PCGF3, migratory proteins(MMP2/9), and the PI3K/AKT signaling pathway-related proteins were assessed by western blot. The expression of PCGF3 mRNA was quantitative analyzed by using 52 pairs of paraffin-embedded tissues from HCC patients. siRNAs-PCGF3 were used to knocked-down PCGF3 expression.

Results: The expression of miR-106b-3p was significantly higher in THP-1 cells and supernatants treated with IFN-exo than those untreated. Significantly increased expression of miR-106b-3p and decreased expression of HBsAg and HBV DNA were observed in Huh7-C2/B3 cells treated with IFN-exo. In addition, miR-106b-3p was directly target to PCGF3. Scratch healing assay and transwell assay showed that either IFN-exo or miRNA-106-3p over-expression, or siRNAs-PCGF3 inhibited migration and invasion of Huh7-C2/B3 cells, and subsequently resulted in suppression of p-AKT/AKT and p-PI3K/PI3K. Notably, the expression level of PCGF3 was significantly lower in HBeAg (+)-HCC tumor tissues than HBeAg (-)-HCC tumor.

Conclusion: IFN-α-induced macrophage-derived miR-106b-3p inhibits HBV replication, HBV- Huh7 cells migration and invasion via regulating PCGF3/PI3K/AKT signaling axis. miR-106b-3p and PCGF3 were potential biomarkers in the prevention and treatment of HBV-HCC.

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经 IFN 处理的巨噬细胞衍生外泌体可通过调节 miR-106b-3p/PCGF3/PI3K/AKT 信号轴阻止 HBV-HCC 迁移和侵袭。

背景：研究发现，来自经IFN-α处理的肝脏非实质性细胞（IFN-exo）的外泌体具有抗病毒活性。不同的研究表明，MiR-106b-3p 在疾病进展中发挥着矛盾的作用。然而，它在 HBV 相关肝细胞癌（HBV-HCC）中的具体作用及其内在机制仍不清楚：方法：将瞬时转染有 HBV-C2 和 B3 质粒的 Huh7 细胞与 IFN-exo 共同培养。收集细胞上清以检测 miR-106b-3p、HBsAg、HBeAg 和 HBV DNA 水平。对细胞增殖、凋亡、迁移和侵袭进行了分析。通过双荧光素酶报告系统确定了 miR-106b-3p 的假定靶标。用 Western 印迹法评估了 PCGF3、迁移蛋白（MMP2/9）和 PI3K/AKT 信号通路相关蛋白的表达。使用 siRNAs-PCGF3 敲低 PCGF3 的表达：结果：经 IFN-exo 处理的 THP-1 细胞和上清液中 miR-106b-3p 的表达明显高于未处理的细胞和上清液。经 IFN-exo 处理的 Huh7-C2/B3 细胞中，miR-106b-3p 的表达明显增加，HBsAg 和 HBV DNA 的表达减少。此外，miR-106b-3p 是 PCGF3 的直接靶标。划痕愈合试验和透孔试验表明，IFN-exo或miRNA-106-3p过表达，或siRNAs-PCGF3都能抑制Huh7-C2/B3细胞的迁移和侵袭，并随后导致p-AKT/AKT和p-PI3K/PI3K的抑制。值得注意的是，PCGF3在HBeAg（+）-HCC肿瘤组织中的表达水平明显低于HBeAg（-）-HCC肿瘤：IFN-α诱导的巨噬细胞源miR-106b-3p通过调节PCGF3/PI3K/AKT信号轴抑制HBV复制、HBV- Huh7细胞迁移和侵袭。

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

Frontiers in Cellular and Infection Microbiology IMMUNOLOGY-MICROBIOLOGY

CiteScore

7.90

自引率

7.00%

发文量

1817

审稿时长

14 weeks

期刊介绍： Frontiers in Cellular and Infection Microbiology is a leading specialty journal, publishing rigorously peer-reviewed research across all pathogenic microorganisms and their interaction with their hosts. Chief Editor Yousef Abu Kwaik, University of Louisville is supported by an outstanding Editorial Board of international experts. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide. Frontiers in Cellular and Infection Microbiology includes research on bacteria, fungi, parasites, viruses, endosymbionts, prions and all microbial pathogens as well as the microbiota and its effect on health and disease in various hosts. The research approaches include molecular microbiology, cellular microbiology, gene regulation, proteomics, signal transduction, pathogenic evolution, genomics, structural biology, and virulence factors as well as model hosts. Areas of research to counteract infectious agents by the host include the host innate and adaptive immune responses as well as metabolic restrictions to various pathogenic microorganisms, vaccine design and development against various pathogenic microorganisms, and the mechanisms of antibiotic resistance and its countermeasures.