title: Reverse engineering the neuroblastoma regulatory network uncovers MAX as one of the master regulators of tumor progression.
abstract: Neuroblastoma is the most common extracranial tumor and a major cause of infant cancer mortality worldwide. Despite its importance, little is known about its molecular mechanisms. A striking feature of this tumor is its clinical heterogeneity. Possible outcomes range from aggressive invasion to other tissues, causing patient death, to spontaneous disease regression or differentiation into benign ganglioneuromas. Several efforts have been made in order to find tumor progression markers. In this work, we have reconstructed the neuroblastoma regulatory network using an information-theoretic approach in order to find genes involved in tumor progression and that could be used as outcome predictors or as therapeutic targets. We have queried the reconstructed neuroblastoma regulatory network using an aggressive neuroblastoma metastasis gene signature in order to find its master regulators (MRs). MRs expression profiles were then investigated in other neuroblastoma datasets so as to detect possible clinical significance. Our analysis pointed MAX as one of the MRs of neuroblastoma progression. We have found that higher MAX expression correlated with favorable patient outcomes. We have also found that MAX expression and protein levels were increased during neuroblastoma SH-SY5Y cells differentiation. We propose that MAX is involved in neuroblastoma progression, possibly increasing cell differentiation by means of regulating the availability of MYC:MAX heterodimers. This mechanism is consistent with the results found in our SH-SY5Y differentiation protocol, suggesting that MAX has a more central role in these cells differentiation than previously reported. Overexpression of MAX has been identified as anti-tumorigenic in other works, but, to our knowledge, this is the first time that the link between the expression of this gene and malignancy was verified under physiological conditions.
authors.affiliation: Departamento de Bioquímica, Núcleo de Bioinformática, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brasil.
authors.forename: Ricardo D'Oliveira
authors.initials: RD
authors.lastname: Albanus
authors.affiliation: Departamento de Bioquímica, Núcleo de Bioinformática, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brasil.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Juliani Siqueira Dalmolin
authors.affiliation: Departamento de Bioquímica, Núcleo de Bioinformática, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brasil.
authors.forename: Mauro Antônio
authors.initials: MA
authors.lastname: Alves Castro
authors.affiliation: Departamento de Bioquímica, Núcleo de Bioinformática, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brasil.
authors.forename: Matheus
authors.initials: M
authors.lastname: Augusto de Bittencourt Pasquali
authors.affiliation: Departamento de Bioquímica, Núcleo de Bioinformática, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brasil.
authors.forename: Vitor
authors.initials: V
authors.lastname: de Miranda Ramos
authors.affiliation: Departamento de Bioquímica, Núcleo de Bioinformática, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brasil.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pens Gelain
authors.affiliation: Departamento de Bioquímica, Núcleo de Bioinformática, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brasil.
authors.forename: José Cláudio
authors.initials: JC
authors.lastname: Fonseca Moreira
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008954:Models, Biological; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; C067850:Myc associated factor X; C082272:TFEC protein, human