Inactivation or Loss of TTP Promotes Invasion in Head and Neck Cancer via Transcript Stabilization and Secretion of MMP9, MMP2, and IL-6

• Published in: Clinical cancer research 2013-03, Vol.19 (5), p.1169-1179
• Main Authors: VAN TUBERGEN, Elizabeth A, BANERJEE, Rajat, BRADFORD, Carol, PRINCE, Mark, WORDEN, Francis P, KIRKWOOD, Keith L, D'SILVA, Nisha J, MIN LIU, BROEK, Robert Vander, LIGHT, Emily, SHIUHYANG KUO, FEINBERG, Stephen E, WILLIS, Amanda L, WOLF, Gregory, CAREY, Thomas
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - genetics; Anemias. Hemoglobinopathies; Animals; Antineoplastic agents; Apoptosis; Biological and medical sciences; Blotting, Western; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Movement; Cell Proliferation; Chick Embryo; Chorioallantoic Membrane - metabolism; Diseases of red blood cells; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Hematologic and hematopoietic diseases; Humans; Immunoprecipitation; Interleukin-6 - genetics; Interleukin-6 - secretion; Luciferases - metabolism; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - secretion; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - secretion; Medical sciences; Neoplasm Invasiveness; Neoplasm Staging; Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmacology. Drug treatments; Platelet diseases and coagulopathies; rap1 GTP-Binding Proteins - genetics; rap1 GTP-Binding Proteins - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA Stability; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Tissue Array Analysis; Tristetraprolin - antagonists & inhibitors; Tristetraprolin - genetics; Tristetraprolin - metabolism; Tumor Cells, Cultured; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-12-2927

Invasion is the critical step in progression of a precancerous lesion to squamous cell carcinoma of the head and neck (HNSCC). Invasion is regulated by multiple proinflammatory mediators. Tristetraprolin (TTP) is an mRNA-degrading protein that regulates multiple proinflammatory mediators. TTP may serve as an excellent treatment target. Rap1 is a ras-like oncoprotein that induces critical signaling pathways. In this study, the role of rap1 in TTP-mediated invasion was investigated. Using complementary approaches, we modulated TTP and altered expression of interleukin (IL)-6 and matrix metalloproteinase (MMP) 2/9, which were quantified by ELISA and zymogram. Invasion was evaluated in vitro using the oral-cancer-equivalent (OCE) three-dimensional model and in vivo in the chick chorioallantoic membrane (CAM). The role of rap1 and p38 were established using knockdown strategies. Downregulation of TTP significantly increased invasion via secretion of MMP9/2 and IL-6. In the novel OCE and CAM invasion models of HNSCC, cells with downregulated TTP destroyed the basement membrane to invade the underlying connective tissue. Rap1 induces p38 mitogen-activated protein kinase (p38)-mediated inactivation of TTP. Inactive TTP enhances transcript stability via binding to the 3'-untranslated region (UTR). High IL-6 and MMP9 are prognostic for poor clinical outcomes in patients with HNSCC. Targeting the rap1-p38-TTP cascade is an attractive novel treatment strategy in HNSCC to concurrently suppress multiple mediators of invasion.