NRF3 suppresses the malignant progression of TNBC by promoting M1 polarization of macrophages via ROS/HMGB1 axis.

IF 4.4 4区医学 Q2 ONCOLOGY

Cancer Biology & Therapy Pub Date : 2024-12-31 Epub Date: 2024-10-23 DOI:10.1080/15384047.2024.2416221

Ping Xing, Zhenzhen Chen, Wenbo Zhu, Bangyi Lin, Mingming Quan

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引用次数: 0

Abstract

Background: Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Due to its lack of targeted therapy options, TNBC remains a significant clinical challenge. In this study, we investigated the role of nuclear respiratory factor 3 (NRF3) and high-mobility group box 1 (HMGB1) in the progression of TNBC.

Methods: The study analyzed NRF3's clinical expression, differentially expressed genes (DEGs), and immune infiltration in TNBC using the TCGA database and bioinformatics tools. Cellular functions of MDA-MB-468 and Hs578t cells were evaluated through MTT, colony formation, transwell, flow cytometry, and western blotting. The regulatory function of NRF3 in TNBC cell lines was assessed using Immunofluorescence, Immunohistochemistry, qRT-PCR, CHIP, luciferase assay, and ELISA. Moreover, a xenograft model was established to investigate the role of NRF3 in TNBC in vivo.

Results: Low expression of NRF3 in TNBC tumors was associated with unfavorable prognosis and transcripts from tumors with higher NRF3 levels were enriched in oxidative stress and immune-related pathways. The subsequent gain- and loss-functional experiments indicated that NRF3 overexpression significantly suppressed malignant phenotypes, MAPK/ERK signaling pathways, and epithelial-mesenchymal transition (EMT), whereas it promoted reactive oxygen species (ROS) levels in TNBC. Further mechanistic exploration showed that NRF3 inhibited TNBC cell function by regulating oxidative stress-related genes to inhibit the MAPK/ERK signaling pathway by promoting the release of HMGB1 via ROS, thereby promoting M1 macrophage polarization.

Conclusion: NRF3 promotes M1 macrophage polarization through the ROS/HMGB1 axis, thereby inhibiting the malignant progression of TNBC. It is expected to become a therapeutic biomarker for TNBC.

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NRF3 通过 ROS/HMGB1 轴促进巨噬细胞的 M1 极化，从而抑制 TNBC 的恶性进展。

背景：三阴性乳腺癌（TNBC三阴性乳腺癌（TNBC）是一种侵袭性很强的乳腺癌。由于缺乏靶向治疗方案，TNBC 仍是一项重大的临床挑战。在这项研究中，我们探讨了核呼吸因子3（NRF3）和高迁移率组盒1（HMGB1）在TNBC进展过程中的作用：研究利用TCGA数据库和生物信息学工具分析了NRF3在TNBC中的临床表达、差异表达基因（DEGs）和免疫浸润。MDA-MB-468和Hs578t细胞的细胞功能通过MTT、集落形成、transwell、流式细胞术和Western印迹进行了评估。通过免疫荧光、免疫组织化学、qRT-PCR、CHIP、荧光素酶检测和ELISA等方法评估了NRF3在TNBC细胞系中的调控功能。此外，还建立了异种移植模型来研究 NRF3 在 TNBC 中的体内作用：结果：NRF3在TNBC肿瘤中的低表达与预后不良有关，NRF3水平较高的肿瘤转录物富含氧化应激和免疫相关通路。随后的增益和缺失功能实验表明，NRF3的过表达能显著抑制TNBC的恶性表型、MAPK/ERK信号通路和上皮-间质转化（EMT），而促进活性氧（ROS）水平。进一步的机理探索表明，NRF3通过调节氧化应激相关基因抑制MAPK/ERK信号通路，通过ROS促进HMGB1的释放，从而促进M1巨噬细胞极化，从而抑制TNBC细胞功能：结论：NRF3通过ROS/HMGB1轴促进M1巨噬细胞极化，从而抑制TNBC的恶性进展。结论：NRF3通过ROS/HMGB1轴促进M1巨噬细胞极化，从而抑制TNBC的恶性进展，有望成为TNBC的治疗生物标志物。

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

Cancer Biology & Therapy 医学-肿瘤学

CiteScore

7.00

自引率

0.00%

发文量

审稿时长

2.3 months

期刊介绍： Cancer, the second leading cause of death, is a heterogenous group of over 100 diseases. Cancer is characterized by disordered and deregulated cellular and stromal proliferation accompanied by reduced cell death with the ability to survive under stresses of nutrient and growth factor deprivation, hypoxia, and loss of cell-to-cell contacts. At the molecular level, cancer is a genetic disease that develops due to the accumulation of mutations over time in somatic cells. The phenotype includes genomic instability and chromosomal aneuploidy that allows for acceleration of genetic change. Malignant transformation and tumor progression of any cell requires immortalization, loss of checkpoint control, deregulation of growth, and survival. A tremendous amount has been learned about the numerous cellular and molecular genetic changes and the host-tumor interactions that accompany tumor development and progression. It is the goal of the field of Molecular Oncology to use this knowledge to understand cancer pathogenesis and drug action, as well as to develop more effective diagnostic and therapeutic strategies for cancer. This includes preventative strategies as well as approaches to treat metastases. With the availability of the human genome sequence and genomic and proteomic approaches, a wealth of tools and resources are generating even more information. The challenge will be to make biological sense out of the information, to develop appropriate models and hypotheses and to translate information for the clinicians and the benefit of their patients. Cancer Biology & Therapy aims to publish original research on the molecular basis of cancer, including articles with translational relevance to diagnosis or therapy. We will include timely reviews covering the broad scope of the journal. The journal will also publish op-ed pieces and meeting reports of interest. The goal is to foster communication and rapid exchange of information through timely publication of important results using traditional as well as electronic formats. The journal and the outstanding Editorial Board will strive to maintain the highest standards for excellence in all activities to generate a valuable resource.