Cell cycle gene networks are associated with melanoma prognosis

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

Research output: Contribution to journalArticle

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Abstract

Background: 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. Methodology/Principal Findings: 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. Conclusions/Significance: 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.

Original languageEnglish
Article numbere34247
JournalPloS one
Volume7
Issue number4
DOIs
Publication statusPublished - Apr 20 2012

Fingerprint

cdc Genes
Gene Regulatory Networks
melanoma
prognosis
Melanoma
cell cycle
Genes
Cells
RNA
Microarrays
Gene expression
cell proliferation
Cell Proliferation
immune response
Apoptosis
cells
apoptosis
Biomarkers
Bayesian networks
Active Immunity

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Wang, L., Hurley, D. G., Watkins, W., Araki, H., Tamada, Y., Muthukaruppan, A., ... Print, C. G. (2012). Cell cycle gene networks are associated with melanoma prognosis. PloS one, 7(4), [e34247]. https://doi.org/10.1371/journal.pone.0034247

Cell cycle gene networks are associated with melanoma prognosis. / Wang, Li; Hurley, Daniel G.; Watkins, Wendy; Araki, Hiromitsu; Tamada, Yoshinori; Muthukaruppan, Anita; Ranjard, Louis; Derkac, Eliane; Imoto, Seiya; Miyano, Satoru; Crampin, Edmund J.; Print, Cristin G.

In: PloS one, Vol. 7, No. 4, e34247, 20.04.2012.

Research output: Contribution to journalArticle

Wang, L, Hurley, DG, Watkins, W, Araki, H, Tamada, Y, Muthukaruppan, A, Ranjard, L, Derkac, E, Imoto, S, Miyano, S, Crampin, EJ & Print, CG 2012, 'Cell cycle gene networks are associated with melanoma prognosis', PloS one, vol. 7, no. 4, e34247. https://doi.org/10.1371/journal.pone.0034247
Wang L, Hurley DG, Watkins W, Araki H, Tamada Y, Muthukaruppan A et al. Cell cycle gene networks are associated with melanoma prognosis. PloS one. 2012 Apr 20;7(4). e34247. https://doi.org/10.1371/journal.pone.0034247
Wang, Li ; Hurley, Daniel G. ; Watkins, Wendy ; Araki, Hiromitsu ; Tamada, Yoshinori ; Muthukaruppan, Anita ; Ranjard, Louis ; Derkac, Eliane ; Imoto, Seiya ; Miyano, Satoru ; Crampin, Edmund J. ; Print, Cristin G. / Cell cycle gene networks are associated with melanoma prognosis. In: PloS one. 2012 ; Vol. 7, No. 4.
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