Abstract 529: Matrix metalloproteinase expression and secretion in papillary thyroid carcinoma

Abstract

Abstract In the last decade, the incidence of thyroid cancer has risen ∼84% and mortality ∼34%. The ACS estimates ∼ 37,200 new cases of thyroid cancer, with 1,630 deaths in 2009. Papillary thyroid carcinoma (PTC) is the most common thyroid and endocrine malignancy, accounting for ∼80% of all thyroid cancer. It typically occurs from a gain-of-function mutation in the RET, RAS or BRAF genes which make up a linear signaling cascade for ERK activation. Recurrent or persistent disease prevails in up to 40% of thyroidectomy cases with a poor prognosis when aggressive cancer is evident. Thus, further research into factors contributing to aggressive disease is merited. Matrix metalloproteinases (MMPs) represent a family of secreted proteases with diverse functions implicated in the pathogeneses of aggressive tumors. Their functions include degrading the extracellular matrix (ECM) to facilitate cell migration, cell signaling through ECM cleavage products that can affect apoptosis and cell growth, and they can act directly on growth factor precursors and receptors. MMP upregulation has been demonstrated in many types of cancers yet its pattern of expression is poorly understood in PTC. Analysis of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in the human PTC cell line, BCPAP, and the normal thyroid cell line, NTHY-ori by protein array and real-time RT-PCR revealed significantly elevated levels of MMPs and decreased levels of TIMP-4. Real time RT-PCR demonstrated the following fold increases in expression in BCPAP compared to NTHY-ori: 16. 9 (SE=0.79) for MMP-1, 1.80 (SE=0.41) for MMP-3, 1.40 (SE=0.08) for MMP-9, 7.12 (SE=2.14) for MMP-10, 12.60 (SE=6.90) for MMP-13 and increased levels of TIMP-4 in NTHY-ori compared to BCPAP of 2.38 (SE=1.04). Protein array data from serum free conditioned media of the cell lines reflected a similar pattern of secreted MMP and TIM4 levels. Fold increases in the optical concentration (determined by spot densitometry) of secreted proteins were detected in BCPAP compared to NTHY-ori of 29.48 (SE=1.92) for MMP-1, 16.80 (SE=1.07) for MMP-3, 1.66 (SE=0.07) for MMP-9, 3.66 (SE=0.55) for MMP-10, 1.59 (SE=0.11) for MMP-13 and increased levels of TIMP-4 in NTHY-ori compared to BCPAP of 1.27 (SE=0.06). For the first time, these results demonstrate increased production and secretion of a group of MMPs and down regulation of TIMP-4 which have been characterized in tumor progression in a PTC cell line. Further investigation into the role these agents play in the tumorgenesis of aggressive PTC may yield insight into future treatment and screening alternatives. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 529.