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01-06-2011 | Research

Expression and Clinical Significance of FAK and Src Proteins in Human Endometrial Adenocarcinoma

Authors: Nikolaos A. Chatzizacharias, Constantinos Giaginis, Elisavet Gatzidou, Gerasimos Tsourouflis, Ioannis Sfiniadakis, Paraskevi Alexandrou, Stamatios E. Theocharis

Published in: Pathology & Oncology Research | Issue 2/2011

Abstract

Focal Adhesion Kinase (FAK) is a protein tyrosine kinase, localised in the focal adhesions, which, upon activation interacts with Src, another tyrosine kinase, regulating several cellular signalling pathways. Both enzymes have been implicated in malignant transformation and disease progression. The aim of the present study was to evaluate the clinical significance of FAK and Src expression in cases of endometrial adenocarcinoma. The total (t) and the activated, phosphorylated (p) forms of FAK and Src proteins were assessed immunohistochemically in tumour specimens obtained from 43 endometrial adenocarcinoma patients and were statistically analyzed in relation to various clinicopathological parameters and tumour proliferative capacity, reflected by Ki-67 labelling index. t-FAK positivity was significantly correlated with FIGO disease stage (p = 0.031), and t-FAK overexpression with patients’ age (p = 0.015). No statistically significant correlation was identified between t-FAK staining intensity, t-Src positivity, overexpression or staining intensity and any of the clinicopathological parameters tested. No significant correlation was found between neither the positivity nor the intensity of staining of either p-FAk or p-Src with any of the parameters under study. Nonetheless, important, but non-significant, trends were identified between t-FAK staining intensity, t-Src positivity and overexpression and patients’ survival (log rank, p = 0.122, p = 0.090 and p = 0.057 respectively). Similarly, p-FAK and p-Src staining characteristics seemed to correlate, even though non-significantly, with patients’ survival (log rank, p = 0.051 and p = 0.070 for p-FAK and p-Src expression, respectively; log rank, p = 0.134 and p = 0.110 for p-FAK and p-Src staining intensity, respectively). These results support an important potential role of FAK-Src signalling in endometrial malignant disease progress and render further research in this field a necessity.

Guan JL, Shalloway D (1992) Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature 358:690–692PubMedCrossRef

Schaller MD, Borgman CA, Cobb BS, Vines RR, Reynolds AB, Parsons JT (1992) pp 125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc Natl Acad Sci USA 89:5192–5196PubMedCrossRef

Hanks SK, Calalb MB, Harper MC, Patel SK (1992) Focal adhesion protein-tyrosine kinase phosphorylated in response to cell attachment to fibronectin. Proc Natl Acad Sci USA 89:8487–8491PubMedCrossRef

Lipfert L, Haimovich B, Schaller MD, Cobb BS, Parsons JT, Brugge JS (1992) Integrin-dependent phosphorylation and activation of the protein tyrosine kinase pp 125FAK in platelets. J Cell Biol 119:905–912PubMedCrossRef

Zachary I, Sinnett-Smith J, Bombesin RE (1992) Vasopressin, and endothelin stimulation of tyrosine phosphorylation in Swiss 3 T3 cells. Identification of a novel tyrosine kinase as a major substrate. J Biol Chem 267:19031–19034PubMed

Zachary I (1997) Focal adhesion kinase. Int J Biochem Cell Biol 29:929–934PubMedCrossRef

Schaller MD, Parsons JT (1994) Focal adhesion kinase and associated proteins. Curr Opin Cell Biol 6:705–710PubMedCrossRef

Salasznyk RM, Klees RF, Williams WA, Boskey A, Plopper GE (2007) Focal adhesion kinase signaling pathways regulate the osteogenic differentiation of human mesenchymal stem cells. Exp Cell Res 313:22–37PubMedCrossRef

Cary LA, Guan JL (1999) Focal adhesion kinase in integrin-mediated signaling. Front Biosci 4:D102–113PubMedCrossRef

10.

Xing Z, Chen HC, Nowlen JK, Taylor SJ, Shalloway D, Guan JL (1994) Direct interaction of v-Src with the focal adhesion kinase mediated by the Src SH2 domain. Mol Biol Cell 5:413–421PubMed

11.

Rahimi N, Hung W, Tremblay E, Saulnier R, Elliott B (1998) c-Src kinase activity is required for hepatocyte growth factor-induced motility and anchorage-independent growth of mammary carcinoma cells. J Biol Chem 273:33714–33721PubMedCrossRef

12.

Hauck CR, Hunter T, Schlaepfer DD (2001) The v-Src SH3 domain facilitates a cell adhesion-independent association with focal adhesion kinase. J Biol Chem 276:17653–17662PubMedCrossRef

13.

Frame MC (2002) Src in cancer: deregulation and consequences for cell behaviour. Biochim Biophys Acta 1602:114–130PubMed

14.

Hauck SDD, CR SDJ (1999) Signaling through focal adhesion kinase. Prog Biophys Mol Biol 71:435–478PubMedCrossRef

15.

Cox BD, Natarajan M, Stettner MR, Gladson CL (2006) New concepts regarding focal adhesion kinase promotion of cell migration and proliferation. J Cell Biochem 99:35–52PubMedCrossRef

16.

MacPhee DJ, Mostachfi H, Han R, Lye SJ, Post M, Caniggia I (2001) Focal adhesion kinase is a key mediator of human trophoblast development. Lab Invest 81:1469–1483PubMed

17.

Furuta Y, Ilic D, Kanazawa S, Takeda N, Yamamoto T, Aizawa S (1995) Mesodermal defect in late phase of gastrulation by a targeted mutation of focal adhesion kinase, FAK. Oncogene 11:1989–1995PubMed

18.

Sorenson CM, Sheibani N (1999) Focal adhesion kinase, paxillin, and bcl-2: analysis of expression, phosphorylation, and association during morphogenesis. Dev Dyn 215:371–382PubMedCrossRef

19.

Shen T-L, Park AY-J, Alcaraz A et al (2005) Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis. J Cell Biol 169:941–952PubMedCrossRef

20.

Talamonti MS, Roh MS, Curley SA, Gallick GE (1993) Increase in activity and level of pp 60c-src in progressive stages of human colorectal cancer. J Clin Invest 91:53–60PubMedCrossRef

21.

Lutz MP, Esser IB, Flossmann-Kast BB et al (1998) Overexpression and activation of the tyrosine kinase Src in human pancreatic carcinoma. Biochem Biophys Res Commun 243:503–508PubMedCrossRef

22.

Verbeek BS, Vroom TM, Adriaansen-Slot SS et al (1996) c-Src protein expression is increased in human breast cancer. An immunohistochemical and biochemical analysis. J Pathol 180:383–388PubMedCrossRef

23.

Ito H, Gardner-Thorpe J, Zinner MJ, Ashley SW, Whang EE (2003) Inhibition of tyrosine kinase Src suppresses pancreatic cancer invasiveness. Surgery 134:221–226PubMedCrossRef

24.

Myoui A, Nishimura R, Williams PJ et al (2003) C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. Cancer Res 63:5028–5033PubMed

25.

Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE (2004) Inhibition of SRC tyrosine kinase impairs inherent and acquired gemcitabine resistance in human pancreatic adenocarcinoma cells. Clin Cancer Res 10:2307–2318PubMedCrossRef

26.

Chatzizacharias NA, Kouraklis GP, Theocharis SE (2008) Clinical significance of FAK expression in human neoplasia. Histol Histopathol 23:629–650PubMed

27.

Laird AD, Cherrington JM (2003) Small molecule tyrosine kinase inhibitors: clinical development of anticancer agents. Expert Opin Investig Drugs 12:51–64PubMedCrossRef

28.

Chatzizacharias NA, Kouraklis GP, Theocharis SE (2007) Focal adhesion kinase: a promising target for anticancer therapy. Expert Opin Ther Targets 11:1315–1328PubMedCrossRef

29.

Livasy CA, Moore D, Cance WG, Lininger RA (2004) Focal adhesion kinase overexpression in endometrial neoplasia. Appl Immunohistochem Mol Morphol 12:342–345PubMedCrossRef

30.

Su JM, Gui L, Zhou YP, Zha XL (2002) Expression of focal adhesion kinase and alpha5 and beta1 integrins in carcinomas and its clinical significance. World J Gastroenterol 8:613–618PubMed

31.

Giaginis CT, Vgenopoulou S, Tsourouflis GS, Politi EN, Kouraklis GP, Theocharis SE (2009) Expression and clinical significance of focal adhesion kinase in the two distinct histological types, intestinal and diffuse, of human gastric adenocarcinoma. Pathol Oncol Res 15:173–181PubMedCrossRef

32.

Chatzizacharias NA, Giaginis C, Diamanto Zizi-Serbetzoglou D et al (2010) Evaluation of the clinical significance of Focal Adhesion Kinase and Src expression in human pancreatic ductal adenocarcinoma. Pancreas 39:930–936PubMedCrossRef

33.

Macwhinnie N, Monaghan H (2004) The use of P53, PTEN, and C-erbB-2 to differentiate uterine serous papillary carcinoma from endometrioid endometrial carcinoma. Int J Gynecol Cancer 14:938–946PubMedCrossRef

34.

Sobel G, Németh J, Kiss A, Lotz G, Szabó I, Udvarhelyi N, Schaff Z, Páska C (2006) Claudin 1 differentiates endometrioid and serous papillary endometrial adenocarcinoma. Gynec Oncol 103:591–598CrossRef

Title: Expression and Clinical Significance of FAK and Src Proteins in Human Endometrial Adenocarcinoma
Authors: Nikolaos A. Chatzizacharias
Constantinos Giaginis
Elisavet Gatzidou
Gerasimos Tsourouflis
Ioannis Sfiniadakis
Paraskevi Alexandrou
Stamatios E. Theocharis
Publication date: 01-06-2011
Publisher: Springer Netherlands
Published in: Pathology & Oncology Research / Issue 2/2011
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI: https://doi.org/10.1007/s12253-010-9310-6

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