This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pós, Z. Articles by Hegyesi, H. Search for Related Content PubMed PubMed Citation Articles by Pós, Z. Articles by Hegyesi, H.

Phenotypic Profiling of Engineered Mouse Melanomas with Manipulated Histamine Production Identifies Histamine H2 Receptor and Rho-C as Histamine-Regulated Melanoma Progression Markers

¹ Hungarian Academy of Sciences, Semmelweis University Molecular Immunology Research Group, ² National Research Institute for Radiobiology and Radiohygiene, ³ Department of Genetics, Cell, and Immunobiology, Semmelweis University, Budapest, Hungary; and ⁴ German Armed Forces, Institute of Radiobiology, Munich, Germany

Requests for reprints: András Falus, Department of Genetics, Cell, and Immunobiology, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary. Phone: 36-1-210-2929; Fax: 36-1-303-6968; E-mail: faland{at}dgci.sote.hu.

In the present study, the impact of acquired neoplastic L-histidine decarboxylase (HDC) expression, and its direct consequence, the release of histamine in the tumor environment, was assessed on melanoma tumor progression. B16-F10 mouse melanoma cells were manipulated via stable transfection, and nine novel transgenic variants were generated in triplicates, constitutively expressing the full-length sense mouse HDC mRNA, a mock control, and an antisense HDC RNA segment, respectively. Establishing both primary skin tumors and lung metastases in C57BL/6 mice, the nine variants with different histamine-releasing capacities were subjected to a comprehensive comparative progression profiling in vivo. Our analyses showed trends of markedly accelerated tumor growth (P < 0.001), and moderately increased metastatic colony-forming potential (P = 0.010) along with rising levels of local histamine production. Using RNase protection assay for screening of the melanoma progression profile, and Western blotting for subsequent result validation, we looked for molecular progression markers affected by melanoma histamine secretion. Investigation of 21 functionally clustered markers associated with tumor proliferation, angiogenesis, invasivity, metastasis formation, local or systemic immunomodulation, and histamine signaling revealed positive correlations between histamine production, tumor histamine H2 receptor and rho-C expression (P < 0.001, P = 0.002, respectively). These observations confirm the involvement of histamine in the molecular machinery of melanoma progression.

This article has been cited by other articles:

				S. B. Wallach-Dayan, A. M. Rubinstein, C. Hand, R. Breuer, and D. Naor DNA vaccination with CD44 variant isoform reduces mammary tumor local growth and lung metastasis Mol. Cancer Ther., June 1, 2008; 7(6): 1615 - 1623. [Abstract] [Full Text] [PDF]

				A. A. Moya-Garcia, J. Ruiz-Pernia, S. Marti, F. Sanchez-Jimenez, and I. Tunon Analysis of the Decarboxylation Step in Mammalian Histidine Decarboxylase: A COMPUTATIONAL STUDY J. Biol. Chem., May 2, 2008; 283(18): 12393 - 12401. [Abstract] [Full Text] [PDF]

				Z. Pos, Z. Wiener, P. Pocza, M. Racz, S. Toth, Z. Darvas, V. Molnar, H. Hegyesi, and A. Falus Histamine Suppresses Fibulin-5 and Insulin-like Growth Factor-II Receptor Expression in Melanoma Cancer Res., March 15, 2008; 68(6): 1997 - 2005. [Abstract] [Full Text] [PDF]

				S.-M. Jangi, M.B. Ruiz-Larrea, F. Nicolau-Galmes, N. Andollo, Y. Arroyo-Berdugo, I. Ortega-Martinez, J. L. Diaz-Perez, and M. D. Boyano Terfenadine-induced apoptosis in human melanoma cells is mediated through Ca2+ homeostasis modulation and tyrosine kinase activity, independently of H1 histamine receptors Carcinogenesis, March 1, 2008; 29(3): 500 - 509. [Abstract] [Full Text] [PDF]

				A. Koncz, M. Pasztoi, M. Mazan, F. Fazakas, E. Buzas, A. Falus, and G. Nagy Nitric Oxide Mediates T Cell Cytokine Production and Signal Transduction in Histidine Decarboxylase Knockout Mice J. Immunol., November 15, 2007; 179(10): 6613 - 6619. [Abstract] [Full Text] [PDF]

				E. M. August, L. Patnaude, J. Hopkins, J. Studts, E. Gautschi, A. Shrutkowski, A. Kronkaitis, M. Brown, A. Kabcenell, and D. Rajotte Development of a High-Throughput Assay to Measure Histidine Decarboxylase Activity J Biomol Screen, October 1, 2006; 11(7): 816 - 821. [Abstract] [PDF]