In papillary thyroid carcinoma, TIMP-1 expression correlates with BRAFV600E mutation status and together with hypoxia-related proteins predicts aggressive behavior View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2013-09

AUTHORS

Marius I. Ilie, Sandra Lassalle, Elodie Long-Mira, Véronique Hofman, Joséphine Zangari, Gilles Bénaim, Alexandre Bozec, Nicolas Guevara, Juliette Haudebourg, Isabelle Birtwisle-Peyrottes, José Santini, Patrick Brest, Paul Hofman

ABSTRACT

BRAF (V600E) causes upregulation of tissue inhibitor of metalloproteinase-1 (TIMP-1), which promotes cell invasion in papillary thyroid carcinoma (PTC). Hypoxia-inducible factor-1α (HIF- α) is regulated by hypoxia and also by the BRAF-mediated signaling pathway in PTC. We assessed the association of expression of TIMP-1, HIF-1α, and hypoxia-inducible carbonic anhydrase IX (CAIX) and XII (CAXII) with clinical parameters in PTC. TPC-1/BRAF (WT) wild-type and BcPAP/BRAF (V600E) -mutated PTC cell lines were selected to study the effects of the BRAF (V600E) mutation and hypoxia on expression in vitro of TIMP-1, CAIX, and CAXII proteins by immunoblotting. Higher expression of all proteins was detected in BcPAP cells exposed to hypoxia. Tissue microarray immunohistochemistry analysis was performed to study protein expression in 114 BRAF-genotyped PTC samples. Expression data on tumor tissue were compared with clinicopathological variables. TIMP-1 expression had a sensitivity of 87 % and a specificity of 83 % in identifying a BRAF mutation (P < 0.001) and was associated with pT stage (P = 0.001), pN stage (P = 0.02), and multifocality (P = 0.03). HIF-1α expression correlated with pT stage (P = 0.05). CAIX expression was associated with pN stage (P = 0.02), and both CAIX (P = 0.004) and CAXII (P = 0.05) were strongly associated with vascular invasion. We conclude that TIMP-1 protein expression is a reliable surrogate marker for BRAF-mutated status in PTC. TIMP-1 and hypoxia-regulated proteins are promising as predictors of aggressiveness in PTC and warrant further investigation as new therapeutic targets for the treatment of highly aggressive forms of PTC. More... »

PAGES

437-444

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s00428-013-1453-x

    DOI

    http://dx.doi.org/10.1007/s00428-013-1453-x

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1011854007

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/23893334


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