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A Novel Isoform of Human Fibroblast Growth Factor 8 Is Induced by Androgens and Associated with Progression of Esophageal Carcinoma

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Abstract

Human esophageal carcinomas occur more frequently in males, suggesting that androgens may play a role in the regulation of gene expression associated with malignant transformation. We previously established an androgen-sensitive squamous cell carcinoma line, KSE-1, from a male patient with esophageal cancer; recently a novel isoform of human fibroblast growth factor 8 (FGF8f, isoform FGF8b) was identified and expressed following androgen stimulation of KSE-1 cells. The predicted amino acid sequence of FGF8f contained an additional 29 amino acids when compared to FGF8b. Flutamide, an androgen antagonist, inhibited both FGF8b and FGF8f transcription in a dose-dependent manner. Tissue analysis from tumors revealed FGF8b expression in 24 of 41 male, but in 0 of 9 female esophageal carcinomas (58.5%), and none in adjacent normal esophageal mucosa. In addition, FGF8f was detected in 9 of 24 FGF8b-positive tumors (37.5%), and this observation was significantly associated with a poor prognosis (P < 0.001). Our observations suggest that androgenic exposure will induce FGF isoforms in tumor cells, and expression of these growth factors is associated with the prevalence and prognosis of esophageal carcinoma in males.

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REFERENCES

  1. Ullrich A, Schlessinger J: Signal transduction by receptors with tyrosine kinase activity. Cell 61:203–211, 1990

    Google Scholar 

  2. Beato M: Gene regulation by steroid hormons. Cell 56:335–344, 1989

    Google Scholar 

  3. Chang C, Salzman A, Yeh S, Young W, Keller E, Lee H-J, Wang C, Mizokami A: Androgen receptor: An overview. Crit Rev Eukaryotic Gene Exp 5:97–125, 1995

    Google Scholar 

  4. Sugimachi K, Watanabe M, Sadanaga N, Ikebe M, Kitamura K, Mori M, Kuwano H: Recent advances in the diagnosis and surgical treatment of patients with carcinoma of the esophagus. J Am Coll Surg 178:363–368, 1994

    Google Scholar 

  5. Yamashita Y, Hirai T, Mukaida H, Kawano K, Toge T, Niimoto M, Hattori T: Detection of androgen receptors in human esophageal cancer. Jpn J Surg 19:195–202, 1989

    Google Scholar 

  6. Matsuoka H, Sugimachi K, Ueo H, Kuwano H, Nakano S, Nakayama M: Sex hormone response of a newly established squamous cell line derived from clinical esophageal carcinoma. Cancer Res 47:4134–4140, 1987

    Google Scholar 

  7. Ueo H, Matsuoka H, Sugimachi K, Kuwano H, Mori M, Akiyoshi T: Inhibitory effects of estrogen on the growth of a human esophageal carcinoma cell line. Cancer Res 50:7212–7215, 1990

    Google Scholar 

  8. Tanaka S, Mori M, Akiyoshi T, Tanaka Y, Mafune K, Wands JR, Sugimachi K: Coexpression of Grb7 with epidermal growth factor receptor or Her2/erbB2 in human advanced esophageal carcinoma. Cancer Res 57:28–31, 1997

    Google Scholar 

  9. Tanaka S, Ito T, Wands JR: Neoplastic transformation induced by insulin receptor substrate-1 overexpression requires an interaction with both Grb2 and Syp signaling molecules. J Biol Chem 271:14610–14616, 1996

    Google Scholar 

  10. Sahlin L, Norstedt G, Eriksson H: Androgen regulation of the insulin-like growth factor-I and the estrogen receptor in rat uterus and liver. J Steroid Biochem Mol Biol 51:57–66, 1994

    Google Scholar 

  11. Yan G, Fukabori Y, Nikolaropoulos S, Wang F, McKeehan WL: Heparin-binding keratinocyte growth factor is a candidate stromal-to-epithelial-cell andromedin. Mol Endocrinol 6:2123–2128, 1992

    Google Scholar 

  12. Tanaka A, Miyamoto K, Minamino N, Takeda M, Sato B, Matsuo H, Matsumoto K: Cloning and characterization of an androgen-induced growth factor essential for the androgendependent growth of mouse mammary carcinoma cells. Proc Natl Acad Sci USA 89:8928–8932, 1992

    Google Scholar 

  13. Olsen NJ, Zhou P, Ong H, Kovacs WJ: Testosterone induces expression of transforming growth factor-beta 1 in the murine thymus. J Steroid Biochem Mol Biol 45:327–332, 1993

    Google Scholar 

  14. Blunt AG, Lawshe A, Cunningham ML, Seto ML, Ornitz DM, MacArthur CA: Overlapping expression and redundant activation of mesenchymal fibroblast growth factor (FGF) receptors by alternatively spliced FGF-8 ligands. J Biol Chem 272:3733–3738, 1997

    Google Scholar 

  15. Ghosh AK, Shankar DB, Shackleford GM, Wu K, T'Ang A, Miller GJ, Zheng J, Roy-Burman P: Molecular cloning and characterization of human FGF8 alternative messenger RNA forms. Cell Growth Diff 7:1425–1434, 1996

    Google Scholar 

  16. Gemel J, Gorry M, Ehrlich GD, MacArthur CA: Structure and sequence of human FGF8. Genomics 35:253–257, 1996

    Google Scholar 

  17. Labrie F: Mechanism of action and pure antiandrogenic properties of flutamide. Cancer 72:3816–3827, 1993

    Google Scholar 

  18. Kanai M, Go¨ke M, Tsunekawa S, Podolsky DK: Signal transduction pathway of human fibroblast growth factor receptor 3. J Biol Chem 272:6621–6628, 1997

    Google Scholar 

  19. Prez-Catro AV, Wilson J, Altherr MR: Genomic organization of the human fibroblast growth factor receptor 3 (FGFR3) gene and comparative sequence analysis with the mouse Ffgr3 gene. Genomics 41:10–16, 1997

    Google Scholar 

  20. MacArthur CA, Shankar DB, Shackleford GM: Fgf-8, activated by proviral insertion, cooperates with the Wnt-1 transgene in murine mammary tumorigenesis. J Virol 69:2501–2507, 1995

    Google Scholar 

  21. Tanaka S, Akiyoshi T, Mori M, Wands JR, Sugimachi K: A novel frizzled gene identified in human esophageal carcinoma that mediates APC/b-catenin signals. Proc Natl Acad Sci USA 95:10164–10169, 1998 NOVEL FGF8 ISOFORM IN ANDROGEN-STIMULATED ESOPHAGEAL CARCINOMA 1021 Digestive Diseases and Sciences, Vol. 46, No. 5 (May 2001)

    Google Scholar 

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Tanaka, S., Ueo, H., Mafune, Ki. et al. A Novel Isoform of Human Fibroblast Growth Factor 8 Is Induced by Androgens and Associated with Progression of Esophageal Carcinoma. Dig Dis Sci 46, 1016–1021 (2001). https://doi.org/10.1023/A:1010753826788

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