Ensemble of Gene Signatures Identifies Novel Biomarkers in Colorectal Cancer Activated through PPARγ and TNFα Signaling

Stefano Maria Pagnotta, Carmelo Laudanna, Massimo Pancione, Lina Sabatino, Carolina Votino, Andrea Remo, Luigi Cerulo, Pietro Zoppoli, Erminia Manfrin, Vittorio Colantuoni, Michele Ceccarelli

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18 Citations (Scopus)


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.

Original languageEnglish
Article numbere72638
JournalPLoS One
Issue number8
Publication statusPublished - 18 Nov 2013
Externally publishedYes


ASJC Scopus subject areas

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

Cite this

Pagnotta, S. M., Laudanna, C., Pancione, M., Sabatino, L., Votino, C., Remo, A., Cerulo, L., Zoppoli, P., Manfrin, E., Colantuoni, V., & Ceccarelli, M. (2013). Ensemble of Gene Signatures Identifies Novel Biomarkers in Colorectal Cancer Activated through PPARγ and TNFα Signaling. PLoS One, 8(8), [e72638]. https://doi.org/10.1371/journal.pone.0072638