Mediator complex subunit 1 promotes oral squamous cell carcinoma progression by activating MMP9 transcription and suppressing CD8 + T cell antitumor immunity.

Autor: Li Z; Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University Institute of Stomatology, 12 Qixiangtai Road, Tianjin, 300070, China., Sun M; Immunology Department, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China., Yang R; Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University Institute of Stomatology, 12 Qixiangtai Road, Tianjin, 300070, China., Wang Z; Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University Institute of Stomatology, 12 Qixiangtai Road, Tianjin, 300070, China., Zhu Q; Immunology Department, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China., Zhang Y; Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University Institute of Stomatology, 12 Qixiangtai Road, Tianjin, 300070, China., Yang H; Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University Institute of Stomatology, 12 Qixiangtai Road, Tianjin, 300070, China., Meng Z; Department of Oral and Maxillofacial Surgery, Tianjin Medical University School and Hospital of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University Institue of Stomatology, 12 Qixiangtai Road, Tianjin, 300070, China. ddsmzs@sina.com., Hu L; Immunology Department, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China. lizhihu@tmu.edu.cn., Sui L; Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University Institute of Stomatology, 12 Qixiangtai Road, Tianjin, 300070, China. suilei@tmu.edu.cn.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2024 Sep 30; Vol. 43 (1), pp. 270. Date of Electronic Publication: 2024 Sep 30.
DOI: 10.1186/s13046-024-03191-9
Abstrakt: Background: The role of Mediator complex subunit 1 (MED1), a pivotal transcriptional coactivator implicated in diverse biological pathways, remains unexplored in the context of oral squamous cell carcinoma (OSCC). This study aims to elucidate the contributory mechanisms and potential impact of MED1 on the progression of OSCC.
Methods: The expression and clinical significance of MED1 in OSCC tissues were evaluated through the bioinformatics analyses. The effects of MED1 on the biological behavior of OSCC cancer cells were assessed both in vitro and in vivo. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP) assay, bioinformatic analysis, CD8 + T cell isolation experiment, coculture experiment, enzyme-linked immunosorbent assay (ELISA), and flow cytometric analysis were employed to elucidate the underlying mechanism through which MED1 operates in the progression of OSCC.
Results: MED1 exhibited upregulation in both OSCC tissues and multiple OSCC cell lines, which correlated with decreased overall survival in patients. In vitro experiments demonstrated that knockdown of MED1 in metastatic OSCC cell lines SCC-9 and UPCI-SCC-154 hindered cell migration and invasion, while overexpression of MED1 promoted these processes. Whereas, MED1 knockdown had no impact on proliferation of cell lines mentioned above. In vivo studies further revealed that downregulation of MED1 effectively suppressed distant metastasis in OSCC. Mechanistically, MED1 enhanced the binding of transcription factors c-Jun and c-Fos to the matrix metalloprotein 9 (MMP9) promoters, resulting in a significant upregulation of MMP9 transcription. This process contributes to the migration and invasion of SCC-9 and UPCI-SCC-154 cells. Furthermore, MED1 modulated the expression of programmed death-ligand 1 (PD-L1) through the Notch signaling pathway, consequently impacting the tumor-killing capacity of CD8 + T cells in the tumor microenvironment.
Conclusions: Our findings indicate that MED1 plays a pivotal role in OSCC progression through the activation of MMP9 transcription and suppression of CD8 + T cell antitumor immunity, suggesting that MED1 may serve as a novel prognostic marker and therapeutic target in OSCC.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje