J Korean Med Sci.  2004 Oct;19(5):710-715. 10.3346/jkms.2004.19.5.710.

Increased Expression of Focal Adhesion Kinase in Thyroid Cancer: Immunohistochemical Study

• Kim SJ
• Park JW
• Yoon JS
• Mok JO
• Kim YJ
• Park HK
• Kim CH
• Byun DW
• Lee YJ
• Jin SY
• Suh KI
• Yoo MH

• KMID: 1733514
• DOI: http://doi.org/10.3346/jkms.2004.19.5.710

Abstract

Focal adhesion kinase (FAK) is a tyrosine kinase that is found in cellular structures called focal adhesions. FAK appears to be a key element in signal transduction pathways involved in cell adhesion and locomotion. FAK is overexpressed in various tumors, including tumors derived from regions of the head and neck, colon, breast, prostate, and liver. In this study, we investigated immunohistochemically whether FAK expression was increased in thyroid cancers. FAK staining was not seen in any of the 20 normal thyroid tissues or the 6 nodular hyperplasia specimens. In contrast, FAK staining was observed in all of 17 papillary carcinomas, 9 follicular carcinomas, 8 medullary carcinomas, and 2 anaplastic carcinomas. Nine of 17 follicular adenomas showed FAK immunoreactivity. FAK was not expressed in normal tissue and nodular hyperplasia, but was expressed in some of the follicular adenoma, and all of the follicular, papillary, medullary and anaplastic thyroid carcinoma. This result indicates that the up-regulation of FAK may play a role in the development of thyroid carcinogenesis.

Keyword

Focal Adhesion Kinase; Protein-Tyrosine Kinase; Thyroid Nodule; Thyroid Neoplasms; Immunohistochemistry; Focal Adhesions

MeSH Terms

Adenoma/*metabolism/pathology
Adult
Aged
Carcinoma, Papillary/*metabolism/pathology
Female
Humans
Immunohistochemistry
Male
Middle Aged
Protein-Tyrosine Kinase/*metabolism
Research Support, Non-U.S. Gov't
Thyroid Neoplasms/*metabolism/pathology
Tumor Markers, Biological/*metabolism

Figure

• 

  Fig. 1 Immunohistochemical expression of FAK in thyroid nodules. (A) normal tissue, (B) nodular hyperplasia, (C) follicular adenoma that shows negative immunostaining, (D) follicular adenoma that shows moderate immunostaining, (E) papillary carcinoma, (F) follicular carcinoma, (G) medullary carcinoma, (H) anaplastic carcinoma (×400); All carcinoma tissues show the strong staining of FAK.

Reference

1. Vander JB, Gaston EA, Dawber TR. The significance of nontoxic thyroid nodules: final report of a 15-year study of the incidence of thyroid malignancy. Ann Intern Med. 1968. 69:537–540.

2. Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell. 1991. 64:327–336.

3. Zetter BR. Adhesion molecules in tumor metastasis. Semin Cancer Biol. 1993. 4:219–229.

4. Schlaepfer DD, Hauck CR, Sieg DJ. Signaling through focal adhesion kinase. Prog Biophys Mol Biol. 1999. 71:435–478.

5. Schaller MD, Borgman CA, Cobb BS, Vines RR, Reynolds AB, Parsons JT. pp125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc Natl Acad Sci USA. 1992. 89:5192–5196.

6. Guan JL, Trevithick JE, Hynes RO. Fibronectin/integrin interaction induces tyrosine phosphorylation of a 120-kDa protein. Cell Regul. 1991. 2:951–964.

7. Kornberg LJ, Earp HS, Turner CE, Prockop C, Juliano RL. Signal transduction by integrins: increased protein tyrosine phosphorylation caused by clustering of beta 1 integrins. Proc Natl Acad Sci USA. 1991. 88:8392–8396.

8. Sinnett-Smith J, Zachary I, Valverde AM, Rozengurt E. Bombesin stimulation of p125 focal adhesion kinase tyrosine phosphorylation. J Biol Chem. 1993. 268:14261–14268.

9. Zachary I, Rozengurt E. Focal adhesion kinase (p125FAK): a point of convergence in the action of neuropeptides, integrins, and oncogenes. Cell. 1992. 71:891–894.

10. Kornberg LJ. Focal adhesion kinase expression in oral cancers. Head Neck. 1998. 20:634–639.

11. Weiner TM, Liu ET, Craven RJ, Cance WG. Expression of focal adhesion kinase gene and invasive cancer. Lancet. 1993. 342:1024–1025.

12. Owens LV, Xu L, Craven RJ, Dent GA, Weiner TM, Kornberg L, Liu ET, Cance WG. Overexpression of the focal adhesion kinase (p125^FAK) in invasive human tumors. Cancer Res. 1995. 55:2752–2755.

13. Glukhova M, Koteliansky V, Sastre X, Thiery JP. Adhesion systems in normal breast and in invasive breast carcinoma. Am J Pathol. 1995. 146:706–716.

14. Owens LV, Xu L, Dent GA, Yang X, Sturge GC, Craven RJ, Cance WG. Focal adhesion kinase as a marker of invasive potential in differentiated human thyroid cancer. Ann Surg Oncol. 1996. 3:100–105.

15. Tremblay L, Hauck W, Aprikian AG, Begin LR, Chapdelaine A, Chevalier S. Focal adhesion kinase (pp125FAK) expression, activation and association with paxillin and p50^csk in human metastatic prostate carcinoma. Int J Cancer. 1996. 68:164–171.

16. Han NM, Fleming RY, Curley SA, Gallick GE. Overexpression of focal adhesion kinase (p125FAK) in human colorectal carcinoma liver metastases: independence from c-src or c-yes activation. Ann Surg Oncol. 1997. 4:264–268.

17. Withers BE, Hanks SK, Fry DW. Correlations between the expression, phosphotyrosine content and enzymatic activity of focal adhesion kinase, pp125FAK, in tumor and nontransformed cells. Cancer Biochem Biophys. 1996. 15:127–139.

18. Cance WG, Harris JE, Iacocca MV, Roche E, Yang X, Chang J, Simkins S, Xu L. Immunohistochemical analyses of focal adhesion kinase expression in benign and malignant human breast and colon tissues: correlation with preinvasive and invasive phenotypes. Clin Cancer Res. 2000. 6:2417–2423.

19. Moon HS, Park WI, Choi EA, Chung HW, Kim SC. The expression and tyrosine phosphorylation of E-cadherin/catenin adhesion complex, and focal adhesion kinase in invasive cervical carcinomas. Int J Gynecol Cancer. 2003. 13:640–646.

20. Zhao JH, Reiske H, Guan JL. Regulation of the cell cycle by focal adhesion kinase. J Cell Biol. 1998. 143:1997–2008.

21. Hungerford JE, Compton MT, Matter ML, Hoffstrom BG, Otey CA. Inhibition of pp125FAK in cultured fibroblasts results in apoptosis. J Cell Biol. 1996. 135:1383–1390.

22. Xu LH, Owens LV, Sturge GC, Yang X, Lui ET, Craven RJ, Cance WG. Attenuation of the expression of the focal adhesion kinase induces apoptosis in tumor cells. Cell Growth Differ. 1996. 7:413–418.

23. Ilic D, Almeida EA, Schlaepfer DD, Dazin P, Aizawa S, Damsky CH. Extracellular matrix survival signals transduced by focal adhesion kinase suppress p53-mediated apoptosis. J Cell Biol. 1998. 143:547–560.

24. Frisch S, Vuori K, Ruoslahti E, Chan-Hui PY. Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol. 1996. 134:793–799.

25. Ilic D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N, Nomura S, Fujimoto J, Okada M, Yamamoto T. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature. 1995. 377:539–544.

26. Owen JD, Ruest PJ, Fry DW, Hanks SK. Induced focal adhesion kinase (FAK) expression in FAK-null cells enhances cell spreading and migration requiring both auto- and activation loop phosphorylation sites and inhibits adhesion-dependent tyrosine phosphorylation of Pyk2. Mol Cell Biol. 1999. 19:4806–4818.

27. Richardson A, Parsons JT. A mechanism for regulation of the adhesion-associated protein tyrosine kinase pp125FAK. Nature. 1996. 380:538–540.

28. Sieg DJ, Hauck CR, Schlaepfer DD. Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. J Cell Sci. 1999. 112:2677–2691.

29. Cary LA, Chang JF, Guan JL. Stimulation of cell migration by overepression of focal adhesion kinase and its association with Src and Fyn. J Cell Sci. 1996. 109:1787–1794.

30. Klemke RL, Leng J, Molander R, Brooks PC, Vuori K, Cheresh DA. CAS/Crk coupling serves as a molecular switch for induction of cell migration. J Cell Biol. 1998. 140:961–972.

31. Xu LH, Yang X, Bradham CA, Brenner DA, Baldwin AS Jr, Craven RJ, Cance WG. The focal adhesion kinase suppresses transformation-associated, anchorage-independent apoptosis in human breast cancer cells. Involvement of death receptor-related signaling pathways. J Biol Chem. 2000. 275:30597–30604.

32. Xu LH, Yang X, Craven RJ, Cance WG. The COOH-terminal domain of the focal adhesion kinase induces loss of adhesion and cell death in human tumor cells. Cell Growth Differ. 1998. 9:999–1005.

33. Almeida EA, Ilic D, Han Q, Hauck CR, Jin F, Kawakatsu H, Shlaepfer DD, Damsky CM. Matrix survival signaling from fibronectin via focal adhesion kinase to c-jun nh (2)-terminal kinase. J Cell Biol. 2000. 149:741–754.

34. Judson PL, He X, Cance WG, Le LV. Overexpression of focal adhesion kinase, a protein tyrosine kinase, in ovarian carcinoma. Cancer. 1999. 86:1551–1556.

35. Rovin JD, Frierson HF Jr, Ledinh W, Parsons JT, Adams RB. Expression of focal adhesion kinase in normal and pathologic human prostate tissues. Prostate. 2002. 53:124–132.

36. Agochiya M, Brunton VG, Owens DW, Parkinson EK, Paraskeva C, Keith WN, Frame MC. Increased dosage and amplification of the focal adhesion kinase gene in human cancer cells. Oncogene. 1999. 18:5646–5653.

37. Kahana O, Micksche M, Witz IP, Yron I. The focal adhesion kinase (p125FAK) is constitutively active in human malignant melanoma. Oncogene. 2002. 21:3969–3977.

38. Kim LT, Fleming JB, Lopez-Guzman C, Nwariaku F. Focal adhesions and associated proteins in medullary thyroid carcinoma cells. J Surg Res. 2003. 111:177–184.

39. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amster HK, Lips CJ, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjold M, Komminoth P, Heudy GN, Mulligan LM. The relationship between specific RET proto-oncogene mutation and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996. 276:1575–1579.

40. Eng C, Mulligan LM. Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and Hirschsprung disease. Hum Mutat. 1997. 9:97–109.

41. Murakami H, Iwashita T, Asai N, Iwata Y, Narumiya S, Takahashi M. Rho-dependent and -independent tyrosine phosphorylation of focal adhesion kinase, paxillin and p130 Cas mediated by Ret kinase. Oncogene. 1999. 18:1975–1982.

42. Gimm O. Thyroid cancer. Cancer Lett. 2001. 163:143–156.