title: Ensemble of gene signatures identifies novel biomarkers in colorectal cancer activated through PPARγ and TNFα signaling.
abstract: We describe a novel bioinformatic and translational pathology approach, gene Signature Finder Algorithm (gSFA) to identify biomarkers associated with Colorectal Cancer (CRC) survival. Here a robust set of CRC markers is selected by an ensemble method. By using a dataset of 232 gene expression profiles, gSFA discovers 16 highly significant small gene signatures. Analysis of dichotomies generated by the signatures results in a set of 133 samples stably classified in good prognosis group and 56 samples in poor prognosis group, whereas 43 remain unreliably classified. AKAP12, DCBLD2, NT5E and SPON1 are particularly represented in the signatures and selected for validation in vivo on two independent patients cohorts comprising 140 tumor tissues and 60 matched normal tissues. Their expression and regulatory programs are investigated in vitro. We show that the coupled expression of NT5E and DCBLD2 robustly stratifies our patients in two groups (one of which with 100% survival at five years). We show that NT5E is a target of the TNF-α signaling in vitro; the tumor suppressor PPARγ acts as a novel NT5E antagonist that positively and concomitantly regulates DCBLD2 in a cancer cell context-dependent manner.
authors.affiliation: Department of Sciences and Technologies, University of Sannio, Benevento, Italy.
authors.forename: Stefano Maria
authors.initials: SM
authors.lastname: Pagnotta
authors.forename: Carmelo
authors.initials: C
authors.lastname: Laudanna
authors.forename: Massimo
authors.initials: M
authors.lastname: Pancione
authors.forename: Lina
authors.initials: L
authors.lastname: Sabatino
authors.forename: Carolina
authors.initials: C
authors.lastname: Votino
authors.forename: Andrea
authors.initials: A
authors.lastname: Remo
authors.forename: Luigi
authors.initials: L
authors.lastname: Cerulo
authors.forename: Pietro
authors.initials: P
authors.lastname: Zoppoli
authors.forename: Erminia
authors.initials: E
authors.lastname: Manfrin
authors.forename: Vittorio
authors.initials: V
authors.lastname: Colantuoni
authors.forename: Michele
authors.initials: M
authors.lastname: Ceccarelli
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism; D000368:Aged; D000465:Algorithms; D014408:Biomarkers, Tumor / Q000235:genetics*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D019295:Computational Biology; D005109:Extracellular Matrix / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000378:metabolism*; D011379:Prognosis; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics*; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C436326:DCBLD2 protein, human; D058851:GPI-Linked Proteins; D008565:Membrane Proteins; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha; D015720:5'-Nucleotidase; C548241:NT5E protein, human