在正常卵巢上皮细胞中敲除 KLHDC8A 可通过 C5a/C5aR/p65 NFκB 信号通路促进促肿瘤巨噬细胞的极化。

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology Pub Date : 2024-12-24 DOI:10.1016/j.cellimm.2024.104913

Jie Fang , Jin Wang , Xinyue Zhao, Yaping Yang, Yujia Xiao

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引用次数: 0

摘要

目的：肿瘤相关巨噬细胞（tumor associated macrophages， TAM）与卵巢癌（Ovarian cancer， OC）的发病有关，但其确切机制尚不清楚。本研究探讨了Kelch Domain Containing 8a （KLHDC8A）在OC中的表达及其与TAM的相关机制。主要方法：基于肿瘤基因组图谱（Tumor Genome Atlas， TCGA）数据库，对正常组织与癌组织差异表达基因进行生物信息学分析。在正常上皮细胞（IOSE80）中敲低KLHDC8A mRNA表达，探讨siKLHDC8A对IOSE80细胞增殖、侵袭、迁移及C5a分泌的影响。用NC-IOSE80细胞、siKLHDC8A-IOSE80细胞（含或不含C5aR拮抗剂）培养基培养thp1来源的巨噬细胞。关键发现：KLHDC8A在OC中低表达，与促瘤巨噬细胞的浸润呈负相关，有助于OC患者的生存。此外，siKLHDC8A促进IOSE80细胞的增殖、侵袭和迁移，导致肿瘤前巨噬细胞的极化，这可以通过C5aR拮抗剂来挽救。意义：我们的研究结果表明，KLHDC8A敲低可能通过C5a/C5aR/p65 NFκB信号通路影响巨噬细胞向促瘤型分化，从而调控OC的发生。它可能作为肿瘤抑制基因在卵巢癌的诊断和治疗中发挥重要作用。

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KLHDC8A knockdown in normal ovarian epithelial cells promoted the polarization of pro-tumoral macrophages via the C5a/C5aR/p65 NFκB signaling pathway

Aims

Tumor-associated macrophages (TAM) is related to Ovarian cancer (OC) pathogenesis, but the exact mechanism remains unclear. This study investigated the expression of Kelch Domain Containing 8 A (KLHDC8A) in OC and the mechanism associated with TAM.

Main methods

Bioinformatics analysis of differential expression genes between normal and OC tissues were analyzed based on the Tumor Genome Atlas (TCGA) databases. KLHDC8A mRNA expression was knocked down in normal epithelial cells (IOSE80), and then the effects of siKLHDC8A on the proliferation, invasion, migration and C5a secretion of IOSE80 cells were explored. THP1-derived macrophages were cultured with medium of NC-IOSE80 cells, siKLHDC8A-IOSE80 cells with or without C5aR antagonists.

Key findings

KLHDC8A was lowly expressed in OC and negatively correlated with the infiltration of tumor-promoting macrophages, contributing to the survival of OC patients. Furthermore, siKLHDC8A promotes the proliferation, invasion and migration of IOSE80 cells and leads to polarization of pro-tumoral macrophages, which can be rescued by C5aR antagonists.

Significance

Our results indicated that KLHDC8A knockdown could modulate the development of OC by affecting macrophage polarization to pro-tumoral type via the C5a/C5aR/p65 NFκB signaling pathway. It may play an essential role as the tumor suppressor genes in diagnosis and treatment of OC.

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来源期刊

Cellular immunology 生物-免疫学

CiteScore

8.20

自引率

2.30%

发文量

102

审稿时长

30 days

期刊介绍： Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered. Research Areas include: • Antigen receptor sites • Autoimmunity • Delayed-type hypersensitivity or cellular immunity • Immunologic deficiency states and their reconstitution • Immunologic surveillance and tumor immunity • Immunomodulation • Immunotherapy • Lymphokines and cytokines • Nonantibody immunity • Parasite immunology • Resistance to intracellular microbial and viral infection • Thymus and lymphocyte immunobiology • Transplantation immunology • Tumor immunity.