Analysis of Thymosin β4 and Vascular Endothelial Cell Growth Factor (VEGF) Expression in Normal Human Tissues Using Tissue Microarray

Tissue microarray를 이용한 사이모신 베타4(Thymosin β4)와 vascular endothelial cell growth factor (VEGF)의 정상 인간 조직 발현 양상 연구

  • Ock, Mee-Sun (Department of Parasitology and Genetics, Kosin University College of Medicine) ;
  • Cha, Hee-Jae (Department of Parasitology and Genetics, Kosin University College of Medicine)
  • 옥미선 (고신대학교 의과대학 기생충학 유전학 교실) ;
  • 차희재 (고신대학교 의과대학 기생충학 유전학 교실)
  • Published : 2009.12.30


Thymosin ${\beta}4$, a small protein containing 43 amino acids, has multi-functional roles in cell physiology. It was first identified as a thymic maturation factor and recently has been shown to accelerate wound healing, hair growth, angiogenesis, tumor growth, and metastasis. It was also reported to play a key role in developing organs, including the nervous system and heart. Thymosin ${\beta}4$ induces the expression of vascular endothelial cell growth factor (VEGF), laminin-5, and other important biologically active genes. Using tissue microarray analysis, we investigated the expression patterns of thymosin ${\beta}4$ and VEGF in various normal human adult tissues. Thymosin ${\beta}4$ was highly expressed in the liver, pancreas, ductal epithelium of the salivary gland, and heart, and moderately expressed in the skin, lung, spleen, lymph node, thymus, ureter, and blood endothelial cells in both the lung and adrenal gland. The expression of VEGF generally co-localized with thymosin ${\beta}4$ and VEGF was highly expressed in the pancreas, ureter, mammary gland, liver, esophagus, and blood endothelial cells in both the lung and adrenal gland. These results suggest that thymosin ${\beta}4$ plays an important role in the function of various organs and since the expression pattern of thymosin ${\beta}4$ co-localized with VEGF, part of that function may be to induce or maintain angiogenesis.

사이모신 베타 4와 VEGF의 발현을 여러 인간 조직에서 tissue microarray를 사용하여 조사하였다. 사이모신 베타 4는 간, 이자, 침샘의 관상피, 심장에서 강한 발현을 보였으며 피부, 폐, 이자, 림프절, 갑상선, 요관, 폐와 부신의 혈관 내피세포 등에서 중간 수준의 발현 양상을 보였다. VEGF의 발현 양상은 대체적으로 사이모신 베타 4와 동일하였으며 이자, 요관, 유선, 간, 식도, 신장, 폐, 부신 등의 혈관 내피세포에서 강하게 발현되었다. 이러한 결과를 통해 사이모신 베타 4는 간, 이자, 침샘의 관상피, 심장에서 중요한 역할을 담당하며 VEGF와 같은 발현 양상을 보여 혈관 신생작용에 관여함을 확인하였다.



  1. Akhter, M., I. Kobayashi, T. Kiyoshima, K. Matsuo, H. Yamaza, H. Wada, J.Y. Honda, X. Ming, and H. Sakai. 2005. Possible functional involvement of thymosin beta 4 in developing tooth germ of mouse lower first molar. Histochem. Cell BioI. 124, 207-213
  2. Anad6n, R, I. Rodriguez Moldes, P. Carpintero, G. Evangelatosc, E. Livianouc, L. Leondiadisc, I. Quintelab, M.C. Cerviflob, and J. Gomez-Marquezet. 2001. Differential expression of thymosins beta(4) and beta(10) during rat cerebellum postnatal development. Brain Res. 894, 255-265
  3. Bock-Marquette, I., A. Saxena, M. D. White, J. M. DiMaio, and D. Srivastava. 2004. Thymosin beta 4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature 432, 466-472
  4. Border, B. G, S. C. Lin, W. S. Griffin, S. Pardue, and M. Morrison-Bogorad. 1993. Alterations in actin-binding beta-thymosin expression accompany neuronal differentiation and migration in rat cerebellum. J. Neurochem. 61, 2104-2114
  5. Cha, H. J., M. J. Jeong, and H. K Kleinman. 2003. Role of thymosin beta 4 in tumor metastasis and angiogenesis. J. Natl. Cancer Inst. 95, 1674-1680
  6. Condon, M. R and A. K. Hall. 1992. Expression of thymosin beta-4 and related genes in developing human brain. J. Mol. Neurosci. 3, 165-170
  7. Dalakas, M. e. and B. D. Trapp. 1986. Thymosin beta 4 is a shared antigen between lymphoid cells and oligo dendrocytes of normal human brain. Ann. Neurol. 19, 349-355
  8. Dathe, V. and B. Brand-Saberi. 2004. Expression of thymosin beta-4 during chick development. Anat. Embryol (Berl). 208, 27-32
  9. Devineni, N., L. S. Minamide, M. Niu, D. Safer, R Verma, J. R Bamburg, and V. T. Nachmias. 1999. A quantitative analysis of G-actin binding proteins and the G-actin pool in developing chick brain. Brain Res. 823, 129-140
  10. Gnecchi, M., H. He, N. Noiseux, O. D. Liang, L. Zhang, F. Morello, H. Mu, L. G Melo, R. E. Pratt, J. S. Ingwall, and V. J. Dzau. 2006. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J. 20, 661-669
  11. Goldstein, A. L., E. Hannappel, and H KKleinman. 2005. Thymosin $\beta$4: actin-sequestering protein moonlights to repair injured tissues. Trends. Mol. Med. 11, 421-429
  12. Gomez-Marquez, J., M. DosH, F. Segade, X. R Bustelo, J. G. Pichel, F. Dominguez, and M. Freire. 1989. Thymosin-beta 4 gene. Preliminary haracterization and expression in tissues, thymic cells, and lymphocytes. J. Immunol. 143, 2740-2744
  13. Gomez-Marquez, J., F. Franco del Amo, P. Carpintero, and R Anadon. 1996. High levels of mouse thymosin beta-4 mRNA in differentiating P19 embryonic cells and during development of cardiovascular tissues. Biochim. Biophys. Acta. 1306, 187-193
  14. Gomez-Marquez, J., J. I. Pedrares, A. Otero, and R Anadon. 1993. Prominent expression of the actin-sequestering peptide Fx gene in the hippocampal region of rat brain. Neurosci. Lett. 152, 41-44
  15. Gondo, H, J. Kudo, J. W. White, C. Barr, P. Selvanayagam, and G F. Saunders. 1987. Differential expression of the human thymosin-beta 4 gene in lymphocytes, macrophages, and granulocytes. J. Immunol. 139, 3840-3848
  16. Grant, D. S., W. Rose, C. Yaen, A. L. Goldstein, J. Martinez, and H. K. Kleinman. 1999. Thymosin beta 4 enhances endothelial cell differentiation and angiogenesis. Angiogenesis 3, 125-135
  17. Hall, A. K. 1994. Molecular interactions between G-actin, DNase I and the beta-thymosins in apoptosis: a hypothesis. Med. Hypotheses 43, 125-131
  18. Hannappel, E. and M. van Kampen. 1987. Determination of thymosin beta 4 in human blood cells and serum. J. Chromatogr. 397, 279-285
  19. Huang, H. C., C. H. Hu, M. C. Tang, W. S. Wang, P. M. Chen, and Y. Su. Thymosin beta 4 triggers an epithelial-mesenchymal transition in colorectal carcinoma by upregulating integrin-linked kinase. Oncogene 26, 2781-2790
  20. Iguchi, K., Y. Usami, K. Hirano, M. Hamatake, M. Shibata, and M. Ishida. 1999. Decreased thymosin beta 4 in apoptosis induced by a variety of antitumor drugs. Biochem. Pharmacol. 57, 1105-1111
  21. Ji, P., S. Diederichs, W. Wang, S. Baing, R Metzger, P. M. Schneider, N. Tidow, B. Brandt, H. Buerger, E. Bulk, M. Thomas, W. E. Berdel, H Serve, and e. MUller-Tidow. 2003. MAL AT-I, a novel noncoding RNA, and thymosin beta 4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 22, 8031-8041
  22. Kobayashi, T., F. Okada, N. Fujii, N. Tomita, S. Ito, H. Tazawa, T. Aoyama, S. K Choi, T. Shibata, H Fujita, and M. Hosokawa. 2002. Thymosin-beta4 regulates motility and metastasis of malignant mouse fibrosarcoma cells. Am. J. Pathol. 160, 869-882
  23. Larsson, L. I. and S. Holck. 2007. Localization of thymosin beta-4 in tumors. Ann. N. Y. Acad. Sci. 1112, 317-325
  24. Larsson, L. I. and S. Holck. 2007. Occurrence of thymosin beta 4 in human breast cancer cells and in other cell types of the tumor microenvironment. Hum. Pathol. 38,114-119
  25. Low, T. L. and A. L. Goldstein. 1982. Chemical characterization of thymosin beta 4. J. BioI. Chem. 257, 1000-1006
  26. Low, T. L., S. K. Hu, and A. L. Goldstein. 1981. Complete amino acid sequence of bovine thymosin $\beta$4: a thymic hormone that induces terminal deoxynucleotidyl transferase activity in thymocyte populations. Proc. Nati. Acad. Sci. USA 78, 1162-1166
  27. Malinda, K. M., A. L. Goldstein, and H. K. Kleinman. 1997. Thymosin beta 4 stimulates directional migration of human umbilical vein endothelial cells. FASEB J. 11, 474-481
  28. Malinda, K. M., G. S. Sidhu, H. Mani, K. Banaudha, R. K. Maheshwari, A. L. Goldstein, and H. K. Kleinman. 1999. Thymosin beta 4 accelerates wound healing. J. Invest. Dermatol. 113, 364-368
  29. Moon, E. Y, J. H. Song, and K. H. Yang. 2007. Actin-sequestering protein, thymosin-beta-4 (TB4), inhibits caspase-3 activation in paclitaxel-induced tumor cell death. Oncol. Res. 16, 507-516
  30. Niu, M. and V. T. Nachmias. 2007. Increased resistance to apoptosis in cells overexpressing thymosin beta four: A role for focal adhesion kinase pp125F AK. Cell Adhes. Commun. 7, 311-320
  31. Philp, D., A. L. Goldstein, and H. K. Kleinman. 2004. Thymosin beta 4 promotes angiogenesis, wound healing and hair follicle development. Mech. Ageing. Dev. 125, 113-115
  32. Philp, D., M. Nguyen, B. Scheremeta, S. St-Surin, A. M. Villa, A. OrgeC H. K. Kleinman, and M. Elkin. 2004. Thymosin beta 4 increases hair growth by activation of hair follicle stem cells. FASEB J. 18, 385-387
  33. Philp, D., S. St-Surin, S., H. J. Cha, H. S. Moon, H. K. Kleinman, and M. Elkin. 2007. Thymosin beta 4 induces hair growth via stem cell migration and differentiation. Ann. N. Y. A cad. Sci. 1112, 95-103
  34. Safer, D., M. Elzinga, and V. T. Nachmias. 1991. Thymosin $\beta$4 and Fx, an actin-sequestering peptide, are indistinguishable. J. BioI. Chem. 266, 4029-4032
  35. Smart, N., C. A. Risebro, A. A. Melville, K. Moses, R. J. Schwartz, K. R. Chien, and P. R. Riley. 2007. Thymosin beta-4 is essential for coronary vessel development and promotes neovascularization via adult epicardium. Ann. N. Y. Acad. Sci. 1112, 171-188
  36. Sosne, G., P. Qiu, P. L. Christopherson, and M. K. Wheater. 2007. Thymosin beta 4 suppression of corneal NFkappaB: a potential anti-inflammatory pathway. Exp. Eye. Res. 84, 663-669
  37. Van Troys, M., D. Dewitte, M. Goethals, M. F. Carlier, J. Vandekerckhove, and C. Ampe. 1996. The actin binding site of thymosin beta 4 mapped by mutational analysis. EMBO J. 15, 201-221
  38. Wang, W. S., P. M. Chen, H. L. Hsiao, H. S. Wang, W. Y. Liang, and Y Suo 2004. Overexpression of the thymosin beta-4 gene is associated with increased invasion of SW480 colon carcinoma cells and the distant metastasis of human colorectal carcinoma. Oncogene 23, 6666-6671
  39. Weller, F. E., M. G. Mutchnick and A. L. Goldstein. 1988. Enzyme immunoassay measurement of thymosin beta 4 in human serum. J. BioI. Response Mod. 7, 91-96
  40. Xu, G. J., E. Hannappel, J. Morgan, J. Hempstead, and B. L. Horecker. 1982. Synthesis of thymosin beta 4 by peritoneal macrophages and adherent spleen cells. Proc. Nati. Acad. Sci. USA 79, 4006-4009
  41. Young, J. D., A. J. Lawrence, A. G. MacLean, B. P. Leung, I. B. McInnes, B. Canas, D. J. C. Pappin, and R. D. Stevenson. 1999. Thymosin beta 4 sulfoxide is an anti-inflammatory agent generated by monocytes in the presence of glucocorticoids. Nat. Med. 5, 1424-1427