Ren Mi, Chen Ling-Ling, Jiang Lin-Yin, Yu Hui-Hui, Ji Hai-Zhou
Department of Oncological Nursing, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian, China.
Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
Apoptosis. 2025 Jun 14. doi: 10.1007/s10495-025-02128-7.
This study aimed to investigate whether CXCL8-CXCR2 axis in regulating M2 macrophage polarization via RASGRP4 related signaling in ovarian cancer. Data from The Cancer Genome Atlas (TCGA) database was used to assess the correlation between CXCR2 expression and M2 macrophage infiltration. THP-1 human monocytic cells were utilized to analyze the effects of CXCL8 on RASGRP4 expression and M2 polarization. In vivo experiments were conducted using xenograft models to evaluate the impact of CXCL8 and RASGRP4 on tumor growth and macrophage polarization. Among the CXCR2 co-expressed genes, RASGRP4 showed the highest positive correlation with M2 macrophage infiltration in ovarian cancer. Higher expression of RASGRP4 is associated with poorer progression-free survival in patients with serous ovarian cancer. CXCR2 knockdown or inhibition (using SB225002) reduced IL-8-induced upregulation of RASGRP4 mRNA and protein in THP-1 cells. Additionally, PLCβ2 silencing attenuated IL-8-induced RASGRP4 expression. Knockdown of RASGRP4 in THP-1 cells reduced M2 polarization, while overexpression restored it. The CXCL8-CXCR2 axis further enhances M2 polarization through RASGRP4-mediated mTOR-STAT3 signaling. In xenograft ovarian tumor models, knockdown of CXCL8, CXCR2, or RASGRP4 reduced tumor growth and M2 macrophage infiltration. In summary, the CXCL8-CXCR2 axis promotes M2 macrophage polarization via RASGRP4-mediated mTOR-STAT3 signaling in ovarian cancer. Targeting this pathway may be a promising therapeutic strategy to reprogram tumor-associated macrophages and enhance treatment efficacy.
本研究旨在探讨卵巢癌中CXCL8 - CXCR2轴是否通过RASGRP4相关信号传导调节M2巨噬细胞极化。利用来自癌症基因组图谱（TCGA）数据库的数据评估CXCR2表达与M2巨噬细胞浸润之间的相关性。使用THP - 1人单核细胞分析CXCL8对RASGRP4表达和M2极化的影响。采用异种移植模型进行体内实验，以评估CXCL8和RASGRP4对肿瘤生长和巨噬细胞极化的影响。在与CXCR2共表达的基因中，RASGRP4在卵巢癌中与M2巨噬细胞浸润显示出最高的正相关性。RASGRP4的高表达与浆液性卵巢癌患者较差的无进展生存期相关。CXCR2基因敲低或抑制（使用SB225002）可降低IL - 8诱导的THP - 1细胞中RASGRP4 mRNA和蛋白的上调。此外，PLCβ2沉默减弱了IL - 8诱导的RASGRP4表达。THP - 1细胞中RASGRP4基因敲低降低了M2极化，而过表达则使其恢复。CXCL8 - CXCR2轴通过RASGRP4介导的mTOR - STAT3信号传导进一步增强M2极化。在异种移植卵巢肿瘤模型中，CXCL8、CXCR2或RASGRP4基因敲低可降低肿瘤生长和M2巨噬细胞浸润。总之，在卵巢癌中，CXCL8 - CXCR2轴通过RASGRP4介导的mTOR - STAT3信号传导促进M2巨噬细胞极化。靶向该通路可能是一种有前景的治疗策略，可重编程肿瘤相关巨噬细胞并提高治疗效果。
