title: Clinicopathologic and Prognostic Significance of Metalloproteinase Tissue Inhibitor-2 Promoters in Tunisian Colorectal Cancer: A Case-Control Study.
abstract: Tissue inhibitors of metalloproteinases (TIMPs) appear to affect many aspects of cancer biology, playing a crucial role in cell signaling by regulating cell growth, apoptosis, invasion, metastasis, angiogenesis, and genomic instability. In the present study, we investigate whether TIMP-2 SNP, TIMP-2 mRNAs, and TIMP-2 protein is associated with susceptibility to colorectal cancer (CRC) in Tunisian population. Taqman and DNA sequencing techniques were used for genotyping, TIMP-2 expression of each genotype was analyzed using semiquantitative RT-PCR and TIMP-2 protein expression was analyzed using immunohistochemistry staining. Our results showed that significantly elevated CRC risk was found in individuals with CC genotype (odds ratio 1.959; 95% confidence interval, 1.055-3.637). Moreover TIMP-2 mRNA expression in the colorectal cell carcinomas was significantly higher compared with the normal colorectal tissue (0.487±0.015 vs. 0.210±0.013) (P<0.05). In addition, serum levels of TIMP-2 were significantly lower in CRC patients than in adenoma patients (P=0.01) and healthy controls (P=0.003). Serum levels of TIMP-2 correlated significantly with tumor stage and TNM stage and were the lowest in CRC patients with stage D,T4,(N1,N2,N3),M(+). In conclusion, our study demonstrate for the first time the distribution and the clinical significance of TIMP-2 promoter polymorphisms, mRNA, protein expression, and serum level in CRC Tunisian patients suggesting that the genotyping and serum level of TIMP-2 as potential markers for susceptibility to CRC will allow a precise and early identification of individuals at high risk and will aid the design of therapeutic modalities and evaluation of treatment outcome.
authors.affiliation: *Unité de biochimie et de biologie moléculaire 02/UR/09-04, Faculté des Sciences de Tunis †Service d'oncologie médicale Hôpital Abderrahmen Mami, Ariana §Service d'anatomopathologie, Institut Salah Azaiez, Tunis, Tunisia ‡Unité d'oncogénétique, Hôpital Arnaud de Villeneuve, Montpellier, Paris, France.
authors.forename: Dalel
authors.initials: D
authors.lastname: Ben Néjima
authors.forename: Yosr
authors.initials: Y
authors.lastname: Ben Zarkouna
authors.forename: Pascal
authors.initials: P
authors.lastname: Pujol
authors.forename: Amor
authors.initials: A
authors.lastname: Gammoudi
authors.forename: Hamouda
authors.initials: H
authors.lastname: Boussen
authors.forename: Mohamed
authors.initials: M
authors.lastname: Manai
mesh_terms: D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics*; D014416:Tunisia
chemical_list: D012333:RNA, Messenger; C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2