title: DUSP1 phosphatase regulates the proinflammatory milieu in head and neck squamous cell carcinoma.
abstract: DUSP1 is a dual-specificity phosphatase that regulates mitogen-activated protein (MAP) kinase activity. Studies have associated loss of DUSP1 expression with certain cancers, but there has been no report of a mechanism by which this supports tumor progression. In this study, we found DUSP1 mRNA and protein decreased in human head and neck squamous cell carcinoma tissues compared with adjacent nontumor controls. To evaluate the impact of this difference, we compared the susceptibility of Dusp1-deficient mice with oral squamous carcinogenesis induced by 4-nitroquinoline 1-oxide. Dusp1-deficient mice displayed enhanced disease progression, characterized by advanced onset, histologic stage, and tumor burden. In a syngeneic model of tumor progression, subcutaneous injection of EO771 cells formed faster-growing tumors in Dusp1-deficient mice, an effect abrogated by inhibition of p38 MAP kinase with SB203580. Histologic and quantitative assessments demonstrated increased inflammation and deregulated chemokine and cytokine expression in Dusp1-deficient tumor tissues. Specifically, proinflammatory cytokine IL1β was elevated. IL1β production was recapitulated ex vivo in primary bone marrow-derived macrophages from Dusp1-deficient mice. Together, our results clearly establish the role of Dusp1 as a tumor suppressor gene that regulates cancer-associated inflammation.
authors.affiliation: Department of Oral Health Sciences and Center for Oral Health Research, Medical University of South Carolina (MUSC), Charleston, South Carolina.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Public Health Sciences, MUSC, Charleston, South Carolina.
authors.forename: J Madison
authors.initials: JM
authors.lastname: Hyer
authors.affiliation: Department of Oral Health Sciences and Center for Oral Health Research, Medical University of South Carolina (MUSC), Charleston, South Carolina.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.
authors.forename: Nisha J
authors.initials: NJ
authors.lastname: D'Silva
authors.affiliation: Department of Oral Health Sciences and Center for Oral Health Research, Medical University of South Carolina (MUSC), Charleston, South Carolina. klkirk@musc.edu.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Kirkwood
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D011725:Pyridines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: C508585:IL1B protein, human; D007093:Imidazoles; D053583:Interleukin-1beta; D011725:Pyridines; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C093642:SB 203580