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Gene expression analysis after receptor tyrosine kinase activation reveals new potential melanoma proteins

BACKGROUND: Melanoma is an aggressive tumor with increasing incidence. To develop accurate prognostic markers and targeted therapies, changes leading to malignant transformation of melanocytes need to be understood. In the Xiphophorus melanoma model system, a mutated version of the EGF receptor Xmrk...

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Autores principales: Teutschbein, Janka, Haydn, Johannes M, Samans, Birgit, Krause, Michael, Eilers, Martin, Schartl, Manfred, Meierjohann, Svenja
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912872/
https://www.ncbi.nlm.nih.gov/pubmed/20663135
http://dx.doi.org/10.1186/1471-2407-10-386
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author Teutschbein, Janka
Haydn, Johannes M
Samans, Birgit
Krause, Michael
Eilers, Martin
Schartl, Manfred
Meierjohann, Svenja
author_facet Teutschbein, Janka
Haydn, Johannes M
Samans, Birgit
Krause, Michael
Eilers, Martin
Schartl, Manfred
Meierjohann, Svenja
author_sort Teutschbein, Janka
collection PubMed
description BACKGROUND: Melanoma is an aggressive tumor with increasing incidence. To develop accurate prognostic markers and targeted therapies, changes leading to malignant transformation of melanocytes need to be understood. In the Xiphophorus melanoma model system, a mutated version of the EGF receptor Xmrk (Xiphophorus melanoma receptor kinase) triggers melanomagenesis. Cellular events downstream of Xmrk, such as the activation of Akt, Ras, B-Raf or Stat5, were also shown to play a role in human melanomagenesis. This makes the elucidation of Xmrk downstream targets a useful method for identifying processes involved in melanoma formation. METHODS: Here, we analyzed Xmrk-induced gene expression using a microarray approach. Several highly expressed genes were confirmed by realtime PCR, and pathways responsible for their induction were revealed using small molecule inhibitors. The expression of these genes was also monitored in human melanoma cell lines, and the target gene FOSL1 was knocked down by siRNA. Proliferation and migration of siRNA-treated melanoma cell lines were then investigated. RESULTS: Genes with the strongest upregulation after receptor activation were FOS-like antigen 1 (Fosl1), early growth response 1 (Egr1), osteopontin (Opn), insulin-like growth factor binding protein 3 (Igfbp3), dual-specificity phosphatase 4 (Dusp4), and tumor-associated antigen L6 (Taal6). Interestingly, most genes were blocked in presence of a SRC kinase inhibitor. Importantly, we found that FOSL1, OPN, IGFBP3, DUSP4, and TAAL6 also exhibited increased expression levels in human melanoma cell lines compared to human melanocytes. Knockdown of FOSL1 in human melanoma cell lines reduced their proliferation and migration. CONCLUSION: Altogether, the data show that the receptor tyrosine kinase Xmrk is a useful tool in the identification of target genes that are commonly expressed in Xmrk-transgenic melanocytes and melanoma cell lines. The identified molecules constitute new possible molecular players in melanoma development. Specifically, a role of FOSL1 in melanomagenic processes is demonstrated. These data are the basis for future detailed analyses of the investigated target genes.
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spelling pubmed-29128722010-07-31 Gene expression analysis after receptor tyrosine kinase activation reveals new potential melanoma proteins Teutschbein, Janka Haydn, Johannes M Samans, Birgit Krause, Michael Eilers, Martin Schartl, Manfred Meierjohann, Svenja BMC Cancer Research Article BACKGROUND: Melanoma is an aggressive tumor with increasing incidence. To develop accurate prognostic markers and targeted therapies, changes leading to malignant transformation of melanocytes need to be understood. In the Xiphophorus melanoma model system, a mutated version of the EGF receptor Xmrk (Xiphophorus melanoma receptor kinase) triggers melanomagenesis. Cellular events downstream of Xmrk, such as the activation of Akt, Ras, B-Raf or Stat5, were also shown to play a role in human melanomagenesis. This makes the elucidation of Xmrk downstream targets a useful method for identifying processes involved in melanoma formation. METHODS: Here, we analyzed Xmrk-induced gene expression using a microarray approach. Several highly expressed genes were confirmed by realtime PCR, and pathways responsible for their induction were revealed using small molecule inhibitors. The expression of these genes was also monitored in human melanoma cell lines, and the target gene FOSL1 was knocked down by siRNA. Proliferation and migration of siRNA-treated melanoma cell lines were then investigated. RESULTS: Genes with the strongest upregulation after receptor activation were FOS-like antigen 1 (Fosl1), early growth response 1 (Egr1), osteopontin (Opn), insulin-like growth factor binding protein 3 (Igfbp3), dual-specificity phosphatase 4 (Dusp4), and tumor-associated antigen L6 (Taal6). Interestingly, most genes were blocked in presence of a SRC kinase inhibitor. Importantly, we found that FOSL1, OPN, IGFBP3, DUSP4, and TAAL6 also exhibited increased expression levels in human melanoma cell lines compared to human melanocytes. Knockdown of FOSL1 in human melanoma cell lines reduced their proliferation and migration. CONCLUSION: Altogether, the data show that the receptor tyrosine kinase Xmrk is a useful tool in the identification of target genes that are commonly expressed in Xmrk-transgenic melanocytes and melanoma cell lines. The identified molecules constitute new possible molecular players in melanoma development. Specifically, a role of FOSL1 in melanomagenic processes is demonstrated. These data are the basis for future detailed analyses of the investigated target genes. BioMed Central 2010-07-21 /pmc/articles/PMC2912872/ /pubmed/20663135 http://dx.doi.org/10.1186/1471-2407-10-386 Text en Copyright ©2010 Teutschbein et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Teutschbein, Janka
Haydn, Johannes M
Samans, Birgit
Krause, Michael
Eilers, Martin
Schartl, Manfred
Meierjohann, Svenja
Gene expression analysis after receptor tyrosine kinase activation reveals new potential melanoma proteins
title Gene expression analysis after receptor tyrosine kinase activation reveals new potential melanoma proteins
title_full Gene expression analysis after receptor tyrosine kinase activation reveals new potential melanoma proteins
title_fullStr Gene expression analysis after receptor tyrosine kinase activation reveals new potential melanoma proteins
title_full_unstemmed Gene expression analysis after receptor tyrosine kinase activation reveals new potential melanoma proteins
title_short Gene expression analysis after receptor tyrosine kinase activation reveals new potential melanoma proteins
title_sort gene expression analysis after receptor tyrosine kinase activation reveals new potential melanoma proteins
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912872/
https://www.ncbi.nlm.nih.gov/pubmed/20663135
http://dx.doi.org/10.1186/1471-2407-10-386
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