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: Xiaoyi Zhang, J Madison Hyer, Hong Yu, Nisha J D'Silva, Keith L Kirkwood
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 24 Pg. 7191-7 (Dec 15 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 25312268 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• IL1B protein, human
• Imidazoles
• Interleukin-1beta
• Pyridines
• RNA, Messenger
• p38 Mitogen-Activated Protein Kinases
• DUSP1 protein, human
• Dual Specificity Phosphatase 1
• SB 203580

Topics

• Animals
• Carcinoma, Squamous Cell (genetics, pathology)
• Dual Specificity Phosphatase 1 (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Head and Neck Neoplasms (genetics, pathology)
• Humans
• Imidazoles (administration & dosage)
• Inflammation (genetics, pathology)
• Interleukin-1beta (biosynthesis)
• MAP Kinase Signaling System (genetics)
• Macrophages (drug effects, metabolism)
• Mice
• Pyridines (administration & dosage)
• RNA, Messenger (biosynthesis)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, biosynthesis)