Work

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

Year: 2024

Type: article

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.

Source: Cancer Biology & Therapy

DOI: 10.1080/15384047.2024.2416221

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

Institutions: Wenzhou Medical University, Zhejiang Taizhou Hospital, Taizhou Central Hospital

Language: English

Topic: Immune cells in cancer

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,970