title: In papillary thyroid carcinoma, TIMP-1 expression correlates with BRAF (V600E) mutation status and together with hypoxia-related proteins predicts aggressive behavior.
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.
authors.affiliation: Laboratory of Clinical and Experimental Pathology, Louis Pasteur Hospital, 30 Voie Romaine, 06001 Nice Cedex 01, France.
authors.forename: Marius I
authors.initials: MI
authors.lastname: Ilie
authors.forename: Sandra
authors.initials: S
authors.lastname: Lassalle
authors.forename: Elodie
authors.initials: E
authors.lastname: Long-Mira
authors.forename: Véronique
authors.initials: V
authors.lastname: Hofman
authors.forename: Joséphine
authors.initials: J
authors.lastname: Zangari
authors.forename: Gilles
authors.initials: G
authors.lastname: Bénaim
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bozec
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guevara
authors.forename: Juliette
authors.initials: J
authors.lastname: Haudebourg
authors.forename: Isabelle
authors.initials: I
authors.lastname: Birtwisle-Peyrottes
authors.forename: José
authors.initials: J
authors.lastname: Santini
authors.forename: Patrick
authors.initials: P
authors.lastname: Brest
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D066298:In Vitro Techniques; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012189:Retrospective Studies; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019715:Tissue Inhibitor of Metalloproteinase-1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII
references.citation: Nat Rev Cancer. 2003 Oct;3(10):721-32
references.pmid: 13130303
references.citation: J Mol Med (Berl). 2007 Dec;85(12):1301-7
references.pmid: 18026916
references.citation: Nat Rev Cancer. 2002 Jan;2(1):38-47
references.pmid: 11902584
references.citation: Neuro Oncol. 2008 Apr;10(2):131-8
references.pmid: 18322268
references.citation: Br J Cancer. 2009 Mar 24;100(6):874-80
references.pmid: 19240720
references.citation: Cancer Res. 2009 Jan 1;69(1):358-68
references.pmid: 19118021
references.citation: Clin Exp Metastasis. 2011 Dec;28(8):793-802
references.pmid: 21789719
references.citation: J Clin Endocrinol Metab. 2008 Nov;93(11):4331-41
references.pmid: 18713817
references.citation: Sci Signal. 2008 Jul 08;1(27):re6
references.pmid: 18612141
references.citation: Endocr Relat Cancer. 2010 Jan 29;17(1):61-72
references.pmid: 19808899
references.citation: Endocr Relat Cancer. 2011 Nov 14;18(6):669-85
references.pmid: 21903858
references.citation: Br J Cancer. 2008 Mar 11;98(5):956-64
references.pmid: 18268492
references.citation: Br J Cancer. 1999 Mar;79(7-8):1234-9
references.pmid: 10098765
references.citation: Cancer. 2000 Jul 1;89(1):202-17
references.pmid: 10897019
references.citation: Exp Cell Res. 2012 Jun 10;318(10):1094-103
references.pmid: 22465225
references.citation: Cancer. 2000 Apr 15;88(8):1902-8
references.pmid: 10760768
references.citation: J Histochem Cytochem. 2006 Oct;54(10):1075-86
references.pmid: 16517973
references.citation: Thyroid. 2008 Nov;18(11):1179-81
references.pmid: 18925842
references.citation: Arch Surg. 2004 Apr;139(4):390-4; discussion 393-4
references.pmid: 15078706
references.citation: Head Neck. 2004 Dec;26(12):1069-83
references.pmid: 15515157
references.citation: J Clin Endocrinol Metab. 2006 Sep;91(9):3667-70
references.pmid: 16772349
references.citation: Endocr Rev. 2007 Dec;28(7):742-62
references.pmid: 17940185
references.citation: Endocr Relat Cancer. 2004 Sep;11(3):571-9
references.pmid: 15369456
references.citation: Front Pharmacol. 2012 Jul 12;3:134
references.pmid: 22807917
references.citation: Br J Cancer. 2003 Apr 7;88(7):1065-70
references.pmid: 12671706
references.citation: Oncogene. 2002 Mar 28;21(14):2245-52
references.pmid: 11948407
references.citation: Cancer Res. 2003 Apr 1;63(7):1454-7
references.pmid: 12670889
references.citation: J Cell Physiol. 2011 Feb;226(2):299-308
references.pmid: 20857482
references.citation: Br J Cancer. 2010 May 25;102(11):1627-35
references.pmid: 20461082
references.citation: Nature. 2002 Jun 27;417(6892):949-54
references.pmid: 12068308
references.citation: Clin Exp Metastasis. 2011 Feb;28(2):91-9
references.pmid: 21053058
references.citation: Cancer Res. 2007 Sep 15;67(18):8615-23
references.pmid: 17875701
references.citation: Nature. 2006 Aug 17;442(7104):779-85
references.pmid: 16915281
references.citation: Int J Breast Cancer. 2012;2012:290854
references.pmid: 22988515
references.citation: Mod Pathol. 2010 Aug;23(8):1052-60
references.pmid: 20473281
references.citation: Clin Cancer Res. 2010 Dec 15;16(24):5928-35
references.pmid: 20962028
references.citation: Int J Cancer. 2011 Apr 1;128(7):1614-23
references.pmid: 20521252
references.citation: J Cell Mol Med. 2010 Apr;14(4):771-94
references.pmid: 20015196
references.citation: World J Surg. 2007 Apr;31(4):838-48
references.pmid: 17347900
references.citation: Virchows Arch. 2001 Feb;438(2):121-8
references.pmid: 11253113
references.citation: Curr Med Chem. 2010;17(17):1839-50
references.pmid: 20345340
references.citation: Surgery. 2008 Jan;143(1):35-42
references.pmid: 18154931
references.citation: Arch Pathol Lab Med. 2008 Mar;132(3):359-72
references.pmid: 18318579
references.citation: J Clin Endocrinol Metab. 2008 Oct;93(10):3943-9
references.pmid: 18682506
references.citation: Arch Immunol Ther Exp (Warsz). 2011 Aug;59(4):301-7
references.pmid: 21625847
references.citation: Hum Pathol. 2013 Mar;44(3):320-8
references.pmid: 23036367
references.citation: Ann Surg Oncol. 2009 Feb;16(2):240-5
references.pmid: 19034577
references.citation: Nature. 2006 May 25;441(7092):437-43
references.pmid: 16724055