Human papillomavirus-related syntaxin 11 reprograms tumor-associated macrophages to induce breast cancer cell apoptosis via PI3K/AKT signaling.

IF 6.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Medicine Pub Date : 2025-09-02 DOI:10.1186/s10020-025-01325-z

Chuan Hu, Tingting Hu, Jian Wen, Zengrong Jia

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引用次数: 0

Abstract

Background: Human papillomavirus (HPV) is closely associated with tumor progression and the tumor microenvironment (TME), but its role in breast cancer (BC), which can be affected by HPV, has not been reported.

Methods: Ten independent BC cohorts were included to generate two HPV-related gene-based signatures. The CIBERSORT and ESTIMATE algorithms were used to quantify the immune cell fraction and TME scores, and the correlations between HPV-related gene-based signatures and scores were analyzed. The expression patterns and clinical significance of STX11 were determined through bioinformatics analysis, and its effects on modulating tumor-associated macrophages (TAMs) were confirmed by real-time qPCR and Western blotting. The anticancer role of STX11 in macrophages and its underlying mechanisms were analyzed in vitro and in vivo.

Results: Two novel HPV-related gene-based signatures were established that can effectively predict the overall survival and disease-free survival of patients with BC. HPV-related gene-based signatures were significantly associated with the immune score and 19 types of immune cells in BC tissues. STX11 was downregulated in BC and was associated with favorable clinical prognosis, and it was expressed mainly in M1 TAMs. Mechanistically, STX11 promoted the M1 polarization of macrophages, and macrophages overexpressing STX11 can inhibit BC proliferation and migration by regulating the PI3K-AKT pathway. In orthotopic BC models, macrophages overexpressing STX11 significantly suppressed tumor growth.

Conclusions: HPV-related risk signatures were constructed, which showed prognostic predictive ability for patients with BC. STX11 is associated with a favorable prognosis in patients with BC and facilitates M1 polarization, and macrophages overexpressing STX11 can inhibit BC malignancy by regulating the PI3K-AKT pathway, suggesting its role as a potential immunotherapeutic candidate.

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人乳头瘤病毒相关syntaxin 11通过PI3K/AKT信号通路重编程肿瘤相关巨噬细胞诱导乳腺癌细胞凋亡

背景：人乳头瘤病毒（HPV）与肿瘤进展和肿瘤微环境（TME）密切相关，但其在可受HPV影响的乳腺癌（BC）中的作用尚未报道。方法：纳入10个独立的BC队列，以生成两个hpv相关的基于基因的签名。使用CIBERSORT和ESTIMATE算法量化免疫细胞分数和TME评分，并分析hpv相关基因特征与评分之间的相关性。通过生物信息学分析确定STX11的表达模式和临床意义，并通过实时荧光定量pcr和Western blotting验证其对肿瘤相关巨噬细胞（tumor associated macrophages, tam）的调节作用。通过体外和体内实验分析STX11在巨噬细胞中的抗癌作用及其机制。结果：建立了两个新的hpv相关基因特征，可以有效预测BC患者的总生存期和无病生存期。hpv相关基因标记与BC组织中的免疫评分和19种免疫细胞显著相关。STX11在BC中下调，与良好的临床预后相关，主要在M1 tam中表达。机制上，STX11促进巨噬细胞M1极化，过表达STX11的巨噬细胞可通过调节PI3K-AKT通路抑制BC的增殖和迁移。在原位BC模型中，过表达STX11的巨噬细胞显著抑制肿瘤生长。结论：构建了hpv相关的风险特征，显示了对BC患者的预后预测能力。STX11与BC患者的良好预后相关，促进M1极化，过表达STX11的巨噬细胞可以通过调节PI3K-AKT通路抑制BC恶性肿瘤，提示其作为潜在的免疫治疗候选蛋白的作用。

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来源期刊

Molecular Medicine 医学-生化与分子生物学

CiteScore

8.60

自引率

0.00%

发文量

137

审稿时长

1 months

期刊介绍： Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.