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Gene expression analyses of primary melanomas reveal CTHRC1 as an important player in melanoma progression

Melanoma is notorious for its high tendency to metastasize and its refractoriness to conventional treatments after metastasis, and the responses to most targeted therapies are short-lived. A better understanding of the molecular mechanisms behind melanoma development and progression is needed to dev...

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Autores principales: Eriksson, Johanna, Le Joncour, Vadim, Nummela, Pirjo, Jahkola, Tiina, Virolainen, Susanna, Laakkonen, Pirjo, Saksela, Olli, Hölttä, Erkki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924771/
https://www.ncbi.nlm.nih.gov/pubmed/26918341
http://dx.doi.org/10.18632/oncotarget.7604
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author Eriksson, Johanna
Le Joncour, Vadim
Nummela, Pirjo
Jahkola, Tiina
Virolainen, Susanna
Laakkonen, Pirjo
Saksela, Olli
Hölttä, Erkki
author_facet Eriksson, Johanna
Le Joncour, Vadim
Nummela, Pirjo
Jahkola, Tiina
Virolainen, Susanna
Laakkonen, Pirjo
Saksela, Olli
Hölttä, Erkki
author_sort Eriksson, Johanna
collection PubMed
description Melanoma is notorious for its high tendency to metastasize and its refractoriness to conventional treatments after metastasis, and the responses to most targeted therapies are short-lived. A better understanding of the molecular mechanisms behind melanoma development and progression is needed to develop more effective therapies and to identify new markers to predict disease behavior. Here, we compared the gene expression profiles of benign nevi, and non-metastatic and metastatic primary melanomas to identify any common changes in disease progression. We identified several genes associated with inflammation, angiogenesis, and extracellular matrix modification to be upregulated in metastatic melanomas. We selected one of these genes, collagen triple helix repeat containing 1 (CTHRC1), for detailed analysis, and found that CTHRC1 was expressed in both melanoma cells and the associated fibroblasts, as well as in the endothelium of tumor blood vessels. Knockdown of CTHRC1 expression by shRNAs in melanoma cells inhibited their migration in Transwell assays and their invasion in three-dimensional collagen and Matrigel matrices. We also elucidated the possible down-stream effectors of CTHRC1 by gene expression profiling of the CTHRC1-knockdown cells. Our analyses showed that CTHRC1 is regulated coordinately with fibronectin and integrin β3 by the pro-invasive and -angiogenic transcription factor NFATC2. We also found CTHRC1 to be a target of TFGβ and BRAF. These data highlight the importance of tumor stroma in melanoma progression. Furthermore, CTHRC1 was recognized as an important mediator of melanoma cell migration and invasion, providing together with its regulators—NFATC2, TGFβ, and BRAF—attractive therapeutic targets against metastatic melanomas.
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spelling pubmed-49247712016-07-13 Gene expression analyses of primary melanomas reveal CTHRC1 as an important player in melanoma progression Eriksson, Johanna Le Joncour, Vadim Nummela, Pirjo Jahkola, Tiina Virolainen, Susanna Laakkonen, Pirjo Saksela, Olli Hölttä, Erkki Oncotarget Research Paper Melanoma is notorious for its high tendency to metastasize and its refractoriness to conventional treatments after metastasis, and the responses to most targeted therapies are short-lived. A better understanding of the molecular mechanisms behind melanoma development and progression is needed to develop more effective therapies and to identify new markers to predict disease behavior. Here, we compared the gene expression profiles of benign nevi, and non-metastatic and metastatic primary melanomas to identify any common changes in disease progression. We identified several genes associated with inflammation, angiogenesis, and extracellular matrix modification to be upregulated in metastatic melanomas. We selected one of these genes, collagen triple helix repeat containing 1 (CTHRC1), for detailed analysis, and found that CTHRC1 was expressed in both melanoma cells and the associated fibroblasts, as well as in the endothelium of tumor blood vessels. Knockdown of CTHRC1 expression by shRNAs in melanoma cells inhibited their migration in Transwell assays and their invasion in three-dimensional collagen and Matrigel matrices. We also elucidated the possible down-stream effectors of CTHRC1 by gene expression profiling of the CTHRC1-knockdown cells. Our analyses showed that CTHRC1 is regulated coordinately with fibronectin and integrin β3 by the pro-invasive and -angiogenic transcription factor NFATC2. We also found CTHRC1 to be a target of TFGβ and BRAF. These data highlight the importance of tumor stroma in melanoma progression. Furthermore, CTHRC1 was recognized as an important mediator of melanoma cell migration and invasion, providing together with its regulators—NFATC2, TGFβ, and BRAF—attractive therapeutic targets against metastatic melanomas. Impact Journals LLC 2016-02-23 /pmc/articles/PMC4924771/ /pubmed/26918341 http://dx.doi.org/10.18632/oncotarget.7604 Text en Copyright: © 2016 Eriksson et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Eriksson, Johanna
Le Joncour, Vadim
Nummela, Pirjo
Jahkola, Tiina
Virolainen, Susanna
Laakkonen, Pirjo
Saksela, Olli
Hölttä, Erkki
Gene expression analyses of primary melanomas reveal CTHRC1 as an important player in melanoma progression
title Gene expression analyses of primary melanomas reveal CTHRC1 as an important player in melanoma progression
title_full Gene expression analyses of primary melanomas reveal CTHRC1 as an important player in melanoma progression
title_fullStr Gene expression analyses of primary melanomas reveal CTHRC1 as an important player in melanoma progression
title_full_unstemmed Gene expression analyses of primary melanomas reveal CTHRC1 as an important player in melanoma progression
title_short Gene expression analyses of primary melanomas reveal CTHRC1 as an important player in melanoma progression
title_sort gene expression analyses of primary melanomas reveal cthrc1 as an important player in melanoma progression
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924771/
https://www.ncbi.nlm.nih.gov/pubmed/26918341
http://dx.doi.org/10.18632/oncotarget.7604
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