EphB2 stem-related and EphA2 progression-related miRNA-based networks in progressive stages of CRC evolution: clinical significance and potential miRNA drivers

Mariangela De Robertis, Tommaso Mazza, Caterina Fusilli, Luisa Loiacono, Maria Luana Poeta, Massimo Sanchez, Emanuela Massi, Giuseppe Lamorte, Maria Grazia Diodoro, Edoardo Pescarmona, Emanuela Signori, Graziano Pesole, Angelo Luigi Vescovi, Jesus Garcia-Foncillas, Vito Michele Fazio

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

EphB2 and EphA2 control stemness and differentiation in the intestinal mucosa, but the way they cooperate with the complex mechanisms underlying tumor heterogeneity and how they affect the therapeutic outcome in colorectal cancer (CRC) patients, remain unclear. MicroRNA (miRNA) expression profiling along with pathway analysis provide comprehensive information on the dysregulation of multiple crucial pathways in CRC. Through a network-based approach founded on the characterization of progressive miRNAomes centered on EphA2/EphB2 signaling during tumor development in the AOM/DSS murine model, we found a miRNA-dependent orchestration of EphB2-specific stem-like properties in earlier phases of colorectal tumorigenesis and the EphA2-specific control of tumor progression in the latest CRC phases. Furthermore, two transcriptional signatures that are specifically dependent on the EphA2/EphB2 signaling pathways were identified, namely EphA2, miR-423-5p, CREB1, ADAMTS14, and EphB2, miR-31-5p, mir-31-3p, CRK, CXCL12, ARPC5, SRC. EphA2- and EphB2-related signatures were validated for their expression and clinical value in 1663 CRC patients. In multivariate analysis, both signatures were predictive of survival and tumor progression. The early dysregulation of miRs-31, as observed in the murine samples, was also confirmed on 49 human tissue samples including preneoplastic lesions and tumors. In light of these findings, miRs-31 emerged as novel potential drivers of CRC initiation. Our study evidenced a miRNA-dependent orchestration of EphB2 stem-related networks at the onset and EphA2-related cancer-progression networks in advanced stages of CRC evolution, suggesting new predictive biomarkers and potential therapeutic targets.

Original languageEnglish (US)
Article number169
JournalMolecular Cancer
Volume17
Issue number1
DOIs
StatePublished - Nov 30 2018

Keywords

  • Biomarkers
  • Cancer stem cells
  • Colorectal cancer
  • EphA2 and EphB2
  • MicroRNA

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

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