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Updated: Oct 31, 2025
Merkel Cell Polyomavirus Infection and Detection
Published on: February 7, 2019
MKP-1 is required to limit myeloid-cell mediated oral squamous cell carcinoma progression and regional extension
Zhenning Li1, Lixia Zhang2, Fa-Yu Liu3
1Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY, USA; Department of Oromaxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Province Key Laboratory of Oral Disease, Shenyang, China; Department of Medical Genetics, China Medical University, Shenyang, China, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China.
Abstract:
Mitogen-activated protein kinases (MAPKs) require MAPK phosphatases (MKPs) for deactivation of MAPK intracellular signaling. MKP-1 (encoded by Dusp1) is a key negative regulator of MAPKs and prior reports have indicated that MKP-1 regulates oral cancer-associated inflammation and leukocyte infiltration.
Objective:
To determine the significance of myeloid-based expression of MKP-1 in oral cancer.
Methods:
The Cancer Genome Atlas (TCGA) was used to address DUSP1 expression in oral squamous cell carcinoma (OSCC). Syngeneic and carcinogen-induced mouse models using global and myeloid-specific Dusp-1 deficient mice with immunophenotypic, histologic, and transcriptomic analyses and in vitro migration assays.
Results:
Data from TCGA indicates the DUSP1 expression is inversely related to oral cancer burden and nodal involvement. Using murine models of OSCC, the role of MKP-1 signaling in tumor associated macrophages (TAMs) was assessed. Dusp1-deficient mice had increased tumor burden and TAM infiltrate with increased M2 macrophage polarization. Transcriptomic signatures of TAMs from Dusp1-deficent mice indicated a pro-metastatic phenotype as well as concomitant differences in myeloid-associated genes, cytokine/chemokine signaling, and Notch signaling consistent with tumor progression. In vitro and in vivo assays revealed mouse OSCC cells had a higher migration rate using TAM cell-free supernatant from Dusp1 deficiency mice compared to controls with enhanced regional cervical lymph node metastasis, respectively. To validate TAM studies using implantable mouse models, an OSCC progression model with conditional myeloid-specific Dusp-1 deficient mice demonstrated enhanced OSCC disease progression, characterized by advanced onset, histological stage, and tumor burden.
Conclusion:
Myeloid-based Dusp1-deficiency increases OSCC burden and metastasis through alteration in TAM recruitment, gene profile, and polarity suggesting that MKP-1 could be a viable target to reprogram TAM to limit local/regional OSCC extension.
Insights
Myeloid-specific MKP-1 (DUSP1) deficiency exacerbates oral cancer progression and metastasis by altering tumor-associated macrophages. Targeting MKP-1 may offer a strategy to control oral squamous cell carcinoma (OSCC) spread.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Mitogen-activated protein kinases (MAPKs) are crucial for intracellular signaling and require MAPK phosphatases (MKPs) for deactivation.
- MKP-1, encoded by DUSP1, is a key negative regulator of MAPKs and has been implicated in oral cancer-associated inflammation and leukocyte infiltration.
Purpose of the Study:
- To investigate the significance of myeloid-specific expression of MKP-1 in oral cancer.
- To determine the role of MKP-1 in regulating tumor-associated macrophages (TAMs) and their impact on oral squamous cell carcinoma (OSCC) progression.
Main Methods:
- Utilized The Cancer Genome Atlas (TCGA) for DUSP1 expression analysis in OSCC.
- Employed syngeneic and carcinogen-induced mouse models with global and myeloid-specific Dusp-1 deficiency.
- Conducted immunophenotypic, histologic, transcriptomic analyses, and in vitro migration assays.
Main Results:
- TCGA data revealed an inverse relationship between DUSP1 expression and oral cancer burden/nodal involvement.
- Dusp1-deficient mice exhibited increased tumor burden, TAM infiltration, and M2 macrophage polarization.
- Transcriptomic analysis of TAMs from Dusp1-deficient mice indicated a pro-metastatic phenotype, altered myeloid-associated genes, and dysregulated cytokine/chemokine and Notch signaling.
- OSCC cells showed increased migration and enhanced cervical lymph node metastasis when exposed to supernatant from Dusp1-deficient TAMs.
- Myeloid-specific Dusp-1 deficiency in OSCC progression models led to advanced onset, histological stage, and tumor burden.
Conclusions:
- Myeloid-based Dusp1 deficiency promotes OSCC progression and metastasis by altering TAM recruitment, gene expression, and polarization.
- MKP-1 represents a potential therapeutic target for reprogramming TAMs to inhibit local and regional OSCC extension.
