Oncotarget

Research Papers:

RNA-seq analysis reveals significant effects of EGFR signalling on the secretome of mesenchymal stem cells

Antonella De Luca _, Cristin Roma, Marianna Gallo, Francesca Fenizia, Francesca Bergantino, Daniela Frezzetti, Susan Costantini and Nicola Normanno

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Oncotarget. 2014; 5:10518-10528. https://doi.org/10.18632/oncotarget.2420

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Abstract

Antonella De Luca1, Cristin Roma2, Marianna Gallo1, Francesca Fenizia2, Francesca Bergantino2, Daniela Frezzetti1, Susan Costantini2, Nicola Normanno1,2

1 Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS, Naples, Italy

2 Centro di Ricerche Oncologiche di Mercogliano (CROM)-Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS, Mercogliano (AV), Italy

Correspondence to:

Nicola Normanno, e-mail: [email protected], [email protected]

Keywords: EGFR, mesenchymal stem cells, tumor microenvironment, RNA-seq

Received: July 31, 2014     Accepted: August 28, 2014     Published: October 29, 2014

ABSTRACT

Bone marrow-derived mesenchymal stem cells (MSCs) contribute to breast cancer progression by releasing soluble factors that sustain tumor progression. MSCs express functional epidermal growth factor receptor (EGFR) and breast cancer cells secrete EGFR-ligands including transforming growth factor-α (TGFα). Using RNA-sequencing, we analysed the whole transcriptome of MSCs stimulated with TGFα. We identified 1,640 highly differentially regulated genes: 967 genes up-regulated with Fold Induction (FI)≥1.50 and 673 genes down-regulated with FI≤0.50. When highly regulated genes were categorized according to GO molecular function classification and KEGG pathways analysis, a large number of genes coding for potentially secreted proteins or surface receptors resulted enriched following TGFα treatment, including VEGFA, IL6, EREG, HB-EGF, LIF, NGF, NRG1, CCL19, CCL2, CCL25 and CXCL3. Secretion of corresponding proteins was confirmed for selected factors. Finally, we identified 4,377 and 4,262 alternatively spliced genes in untreated and TGFα-treated MSCs, respectively. Among these, an unannotated splice variant of VEGFA coding for a secreted VEGF protein of 172 aminoacids (VEGFA172), was found only in MSCs stimulated with TGFα. These findings suggest that EGFR activation in MSCs leads to a significant change in the expression of a wide array of genes coding for secreted proteins that can significantly enhance tumor progression.


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