Cell cycle gene networks are associated with melanoma prognosis.

<h4>Background</h4>Our understanding of the molecular pathways that underlie melanoma remains incomplete. Although several published microarray studies of clinical melanomas have provided valuable information, we found only limited concordance between these studies. Therefore, we took an...

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Autores principales:	Li Wang, Daniel G Hurley, Wendy Watkins, Hiromitsu Araki, Yoshinori Tamada, Anita Muthukaruppan, Louis Ranjard, Eliane Derkac, Seiya Imoto, Satoru Miyano, Edmund J Crampin, Cristin G Print
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/569980040a424319b199786c83cca5d8
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spelling	oai:doaj.org-article:569980040a424319b199786c83cca5d82021-11-18T07:21:29ZCell cycle gene networks are associated with melanoma prognosis.1932-620310.1371/journal.pone.0034247https://doaj.org/article/569980040a424319b199786c83cca5d82012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22536322/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Our understanding of the molecular pathways that underlie melanoma remains incomplete. Although several published microarray studies of clinical melanomas have provided valuable information, we found only limited concordance between these studies. Therefore, we took an in vitro functional genomics approach to understand melanoma molecular pathways.<h4>Methodology/principal findings</h4>Affymetrix microarray data were generated from A375 melanoma cells treated in vitro with siRNAs against 45 transcription factors and signaling molecules. Analysis of this data using unsupervised hierarchical clustering and Bayesian gene networks identified proliferation-association RNA clusters, which were co-ordinately expressed across the A375 cells and also across melanomas from patients. The abundance in metastatic melanomas of these cellular proliferation clusters and their putative upstream regulators was significantly associated with patient prognosis. An 8-gene classifier derived from gene network hub genes correctly classified the prognosis of 23/26 metastatic melanoma patients in a cross-validation study. Unlike the RNA clusters associated with cellular proliferation described above, co-ordinately expressed RNA clusters associated with immune response were clearly identified across melanoma tumours from patients but not across the siRNA-treated A375 cells, in which immune responses are not active. Three uncharacterised genes, which the gene networks predicted to be upstream of apoptosis- or cellular proliferation-associated RNAs, were found to significantly alter apoptosis and cell number when over-expressed in vitro.<h4>Conclusions/significance</h4>This analysis identified co-expression of RNAs that encode functionally-related proteins, in particular, proliferation-associated RNA clusters that are linked to melanoma patient prognosis. Our analysis suggests that A375 cells in vitro may be valid models in which to study the gene expression modules that underlie some melanoma biological processes (e.g., proliferation) but not others (e.g., immune response). The gene expression modules identified here, and the RNAs predicted by Bayesian network inference to be upstream of these modules, are potential prognostic biomarkers and drug targets.Li WangDaniel G HurleyWendy WatkinsHiromitsu ArakiYoshinori TamadaAnita MuthukaruppanLouis RanjardEliane DerkacSeiya ImotoSatoru MiyanoEdmund J CrampinCristin G PrintPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 4, p e34247 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Li Wang Daniel G Hurley Wendy Watkins Hiromitsu Araki Yoshinori Tamada Anita Muthukaruppan Louis Ranjard Eliane Derkac Seiya Imoto Satoru Miyano Edmund J Crampin Cristin G Print Cell cycle gene networks are associated with melanoma prognosis.
description	<h4>Background</h4>Our understanding of the molecular pathways that underlie melanoma remains incomplete. Although several published microarray studies of clinical melanomas have provided valuable information, we found only limited concordance between these studies. Therefore, we took an in vitro functional genomics approach to understand melanoma molecular pathways.<h4>Methodology/principal findings</h4>Affymetrix microarray data were generated from A375 melanoma cells treated in vitro with siRNAs against 45 transcription factors and signaling molecules. Analysis of this data using unsupervised hierarchical clustering and Bayesian gene networks identified proliferation-association RNA clusters, which were co-ordinately expressed across the A375 cells and also across melanomas from patients. The abundance in metastatic melanomas of these cellular proliferation clusters and their putative upstream regulators was significantly associated with patient prognosis. An 8-gene classifier derived from gene network hub genes correctly classified the prognosis of 23/26 metastatic melanoma patients in a cross-validation study. Unlike the RNA clusters associated with cellular proliferation described above, co-ordinately expressed RNA clusters associated with immune response were clearly identified across melanoma tumours from patients but not across the siRNA-treated A375 cells, in which immune responses are not active. Three uncharacterised genes, which the gene networks predicted to be upstream of apoptosis- or cellular proliferation-associated RNAs, were found to significantly alter apoptosis and cell number when over-expressed in vitro.<h4>Conclusions/significance</h4>This analysis identified co-expression of RNAs that encode functionally-related proteins, in particular, proliferation-associated RNA clusters that are linked to melanoma patient prognosis. Our analysis suggests that A375 cells in vitro may be valid models in which to study the gene expression modules that underlie some melanoma biological processes (e.g., proliferation) but not others (e.g., immune response). The gene expression modules identified here, and the RNAs predicted by Bayesian network inference to be upstream of these modules, are potential prognostic biomarkers and drug targets.
format	article
author	Li Wang Daniel G Hurley Wendy Watkins Hiromitsu Araki Yoshinori Tamada Anita Muthukaruppan Louis Ranjard Eliane Derkac Seiya Imoto Satoru Miyano Edmund J Crampin Cristin G Print
author_facet	Li Wang Daniel G Hurley Wendy Watkins Hiromitsu Araki Yoshinori Tamada Anita Muthukaruppan Louis Ranjard Eliane Derkac Seiya Imoto Satoru Miyano Edmund J Crampin Cristin G Print
author_sort	Li Wang
title	Cell cycle gene networks are associated with melanoma prognosis.
title_short	Cell cycle gene networks are associated with melanoma prognosis.
title_full	Cell cycle gene networks are associated with melanoma prognosis.
title_fullStr	Cell cycle gene networks are associated with melanoma prognosis.
title_full_unstemmed	Cell cycle gene networks are associated with melanoma prognosis.
title_sort	cell cycle gene networks are associated with melanoma prognosis.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/569980040a424319b199786c83cca5d8
work_keys_str_mv	AT liwang cellcyclegenenetworksareassociatedwithmelanomaprognosis AT danielghurley cellcyclegenenetworksareassociatedwithmelanomaprognosis AT wendywatkins cellcyclegenenetworksareassociatedwithmelanomaprognosis AT hiromitsuaraki cellcyclegenenetworksareassociatedwithmelanomaprognosis AT yoshinoritamada cellcyclegenenetworksareassociatedwithmelanomaprognosis AT anitamuthukaruppan cellcyclegenenetworksareassociatedwithmelanomaprognosis AT louisranjard cellcyclegenenetworksareassociatedwithmelanomaprognosis AT elianederkac cellcyclegenenetworksareassociatedwithmelanomaprognosis AT seiyaimoto cellcyclegenenetworksareassociatedwithmelanomaprognosis AT satorumiyano cellcyclegenenetworksareassociatedwithmelanomaprognosis AT edmundjcrampin cellcyclegenenetworksareassociatedwithmelanomaprognosis AT cristingprint cellcyclegenenetworksareassociatedwithmelanomaprognosis
_version_	1718423596232081408

Cell cycle gene networks are associated with melanoma prognosis.

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