• Clin Cancer Res · Mar 2013

    Inactivation or loss of TTP promotes invasion in head and neck cancer via transcript stabilization and secretion of MMP9, MMP2, and IL-6.

    • Elizabeth A Van Tubergen, Rajat Banerjee, Min Liu, Robert Vander Broek, Emily Light, Shiuhyang Kuo, Stephen E Feinberg, Amanda L Willis, Gregory Wolf, Thomas Carey, Carol Bradford, Mark Prince, Francis P Worden, Keith L Kirkwood, and Nisha J D'Silva.
    • Periodontics and Oral Medicine, Oral Maxillofacial Surgery, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA.
    • Clin Cancer Res. 2013 Mar 1; 19 (5): 1169-79.

    PurposeInvasion 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.Experimental DesignUsing 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.ResultsDownregulation 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.ConclusionsTargeting the rap1-p38-TTP cascade is an attractive novel treatment strategy in HNSCC to concurrently suppress multiple mediators of invasion.©2012 AACR.

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