MKP-1 is required to limit myeloid-cell mediated oral squamous cell carcinoma progression and regional extension

Zhenning Li; Lixia Zhang; Fa-Yu Liu; Peng Li; Jing He; Cameron L Kirkwood; Jiho Sohn; Jon M Chan; William J Magner; Keith L Kirkwood

doi:10.1016/j.oraloncology.2021.105401

MKP-1 is required to limit myeloid-cell mediated oral squamous cell carcinoma progression and regional extension

Oral Oncol. 2021 Sep:120:105401. doi: 10.1016/j.oraloncology.2021.105401. Epub 2021 Jun 26.

Authors

Zhenning Li¹, Lixia Zhang², Fa-Yu Liu³, Peng Li⁴, Jing He³, Cameron L Kirkwood⁵, Jiho Sohn⁶, Jon M Chan⁷, William J Magner⁷, Keith L Kirkwood⁸

Affiliations

¹ Department 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.
² Department of Medical Genetics, China Medical University, Shenyang, China, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China.
³ Department 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.
⁴ Department of Medical Genetics, China Medical University, Shenyang, China, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China,; Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY, USA.
⁵ Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY, USA.
⁶ Department of Medicine, University at Buffalo, Buffalo, NY, USA.
⁷ Department of Head and Neck/Plastic and Reconstructive Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
⁸ Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY, USA; Department of Head and Neck/Plastic and Reconstructive Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. Electronic address: klkirk@buffalo.edu.

PMID: 34182221
DOI: 10.1016/j.oraloncology.2021.105401

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.

Keywords: MKP-1; Metastasis; Oral squamous cell carcinoma; Tumor associated macrophage; Tumor microenvironment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Polarity
Disease Progression
Lymphatic Metastasis
Mice
Mitogen-Activated Protein Kinases* / genetics
Mouth Neoplasms* / genetics
Squamous Cell Carcinoma of Head and Neck* / genetics
Transcriptome
Tumor-Associated Macrophages

Substances

Mitogen-Activated Protein Kinases