Tumor-associated macrophages induce epithelial-mesenchymal transition and promote lung metastasis in breast cancer by activating the IL-6/STAT3/TGM2 axis

• Published in: International immunopharmacology 2024-12, Vol.143 (Pt 2), p.113387, Article 113387
• Main Authors: Qi, Yana, Li, Ranran, Han, Mingyong
• Format: Article
• Language: English
• Subjects: Animals; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; GTP-Binding Proteins - genetics; GTP-Binding Proteins - metabolism; Humans; Interleukin-6; Interleukin-6 - genetics; Interleukin-6 - metabolism; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Protein Glutamine gamma Glutamyltransferase 2 - metabolism; Signal Transduction; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; TGM2; Transglutaminases - genetics; Transglutaminases - metabolism; Tumor Microenvironment; Tumor-associated macrophages; Tumor-Associated Macrophages - immunology; Tumor-Associated Macrophages - metabolism
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.113387

•TAMs promote breast cancer cells invasion and migration in vitro and in vivo.•TGM2 was potential mediator for TAMs-mediated breast cancer tumorigenes and metastasis.•TAMs derived IL-6 to induced TGM2 expression through JAK/STAT3 phosphorylation.•STAT3 induced expression of TGM2 by directly binding to its promoter. Breast cancer is one of the most common tumors in the world and metastasis is the major cause of tumor-related death. Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and often associated with cancer metastasis. Nevertheless, the mechanism by which TAMs regulate breast cancer metastasis remain unclear. In this study, we found that transglutaminase 2 (TGM2) could serve as a crucial target in the modulation of TAMs-induced epithelial-mesenchymal transition (EMT) and invasion of breast cancer cells. Further analysis revealed that IL-6 secreted from TAMs, which was capable of inducing TGM2 expression through the activation of the JAK/STAT3 signaling pathway. Subsequent luciferase reporter assays demonstrated that STAT3 binds to the TGM2 promoter region, thereby transcriptionally enhancing TGM2 expression. In conclusion, our current research has identified the IL-6/STAT3/TGM2 axis as a pivotal regulator in breast tumorigenesis caused by TAMs, presenting a novel target for the treatment of breast cancer.