High expression of formin-2 can promote ovarian cancer chemoresistance via immunosuppressive macrophages

IF 3.1 4区生物学 Q1 GENETICS & HEREDITY

Functional & Integrative Genomics Pub Date : 2025-12-20 DOI:10.1007/s10142-025-01766-z

Shuo Feng, Yaping Wang, Ran Ren, Xiaotong Wang, Lu Han

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引用次数: 0

Abstract

Ovarian cancer (OC) remains a major threat to women’s health, with chemoresistance driven by the immunosuppressive tumor microenvironment. Formin-2 (FMN2), a cytoskeletal regulator, was investigated for its role in OC chemoresistance and macrophage polarization. Bioinformatics analysis identified high FMN2 expression in chemotherapy-resistant OC cell lines, validated experimentally. Stable FMN2 knockdown cell lines were generated via lentiviral transfection. Functional assays revealed that FMN2 overexpression conferred chemoresistance in vitro and in vivo and promoted M2 macrophage polarization via the CCL2/JAK2/STAT3 pathway. Co-culture with M2 macrophages enhanced cisplatin (DDP) resistance in OC cells, mediated by CXCL1 secretion, which activated the epithelial-mesenchymal transition (EMT) pathway. Clinically, FMN2 levels correlated with CCL2 and CD206 (M2 marker) in platinum-resistant patients, and high FMN2, CCL2, or CD206 expression predicted poorer overall and disease-free survival. This study identifies FMN2 as a key mediator of chemoresistance and immune evasion in OC, proposing FMN2-CCL2-CD206 signaling and macrophage-derived CXCL1 as therapeutic targets and prognostic markers for chemotherapy response.

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高表达的formin-2可通过免疫抑制巨噬细胞促进卵巢癌化疗耐药

卵巢癌（OC）仍然是妇女健康的主要威胁，由免疫抑制肿瘤微环境驱动的化疗耐药。Formin-2 （FMN2）是一种细胞骨架调节剂，研究了其在OC化疗耐药和巨噬细胞极化中的作用。生物信息学分析发现FMN2在化疗耐药OC细胞系中高表达，实验验证。通过慢病毒转染生成稳定的FMN2敲低细胞系。功能分析显示，FMN2过表达在体外和体内产生化学耐药，并通过CCL2/JAK2/STAT3途径促进M2巨噬细胞极化。与M2巨噬细胞共培养可增强OC细胞对顺铂（DDP）的耐药性，这是由CXCL1分泌介导的，CXCL1分泌激活了上皮-间质转化（EMT）途径。临床上，在铂耐药患者中，FMN2水平与CCL2和CD206 （M2标记物）相关，FMN2、CCL2或CD206高表达预示较差的总生存期和无病生存期。本研究确定FMN2是OC化疗耐药和免疫逃避的关键介质，提出FMN2- ccl2 - cd206信号和巨噬细胞来源的CXCL1作为化疗反应的治疗靶点和预后标志物。

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

Functional & Integrative Genomics 生物-遗传学

CiteScore

3.50

自引率

3.40%

发文量

审稿时长

2 months

期刊介绍： Functional & Integrative Genomics is devoted to large-scale studies of genomes and their functions, including systems analyses of biological processes. The journal will provide the research community an integrated platform where researchers can share, review and discuss their findings on important biological questions that will ultimately enable us to answer the fundamental question: How do genomes work?