Phenotypic profiling of engineered mouse melanomas with manipulated histamine production identifies histamine H2 receptor and rho-C as histamine-regulated melanoma progression markers.
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.
Pós
Zoltán
Z
Hungarian Academy of Sciences, Semmelweis University Molecular Immunology Research Group, National Research Institute for Radiobiology and Radiohygiene, Department of Genetics, Cell, and Immunobiology, Semmelweis University, Budapest, Hungary.
Sáfrány
Géza
G
Müller
Kerstin
K
Tóth
Sára
S
Falus
András
A
Hegyesi
Hargita
H
D000818:Animals; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006632:Histamine / Q000096:biosynthesis*; D006636:Histamine Release / Q000502:physiology; D006640:Histidine Decarboxylase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D008546:Melanoma, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D011970:Receptors, Histamine H2 / Q000378:metabolism*; D014162:Transfection; D018631:ras Proteins; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D000075024:rhoC GTP-Binding Protein
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D011970:Receptors, Histamine H2; D006632:Histamine; C512911:Rhoc protein, mouse; D018631:ras Proteins; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein; D006640:Histidine Decarboxylase