Interleukin-34 sustains pro-tumorigenic signals in colon cancer tissue

Abstract

// Eleonora Franzè 1 , Vicenzo Dinallo 1 , Angela Rizzo 1 , Martina Di Giovangiulio 1 , Gerolamo Bevivino 1 , Carmine Stolfi 1 , Flavio Caprioli 2 , Alfredo Colantoni 1 , Angela Ortenzi 1 , Antonio Di Grazia 1 , Giuseppe Sica 3 , Pier Paolo Sileri 3 , Piero Rossi 3 and Giovanni Monteleone 1 1 Department of Systems Medicine, University of Rome “TOR VERGATA”, Rome, Italy 2 Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy 3 Department of Surgery, University “TOR VERGATA” of Rome, Rome, Italy Correspondence to: Giovanni Monteleone, email: [e-mail] Keywords: IL-34; colorectal cancer; tumorigenesis; M-CSF-1; ERK 1/2 Received: July 29, 2017      Accepted: November 17, 2017      Published: December 15, 2017 ABSTRACT Interleukin-34 (IL-34), a cytokine produced by a wide range of cells, binds to the macrophage colony-stimulating factor receptor (M-CSFR-1) and receptor-type protein-tyrosine phosphatase zeta (PTP-z) and controls myeloid cell differentiation, proliferation and survival. various types of cancers over-express IL-34 but the role of the cytokine in colorectal cancer (CRC) remains unknown. We here investigated the expression and functional role of IL-34 in CRC. A more pronounced expression of IL-34 was seen in CRC samples as compared to matched normal/benign colonic samples and this occurred at both RNA and protein level. Immunohistochemical analysis of CRC tissue samples showed that both cancer cells and lamina propria mononuclear cells over-expressed IL-34. Additionally, CRC cells expressed both M-CSFR-1 and PTP-z, thus suggesting that CRC cells can be responsive to IL-34. Indeed, stimulation of DLD-1 cancer cells with IL-34, but not with MSCF1, enhanced the cell proliferation and cell invasion without affecting cell survival. Analysis of intracellular signals underlying the mitogenic effect of IL-34 revealed that the cytokine enhanced activation of ERK1/2 and pharmacologic inhibition of ERK1/2 abrogated IL-34-driven cell proliferation. Consistently, IL-34 knockdown in HT-29 cells with a specific IL-34 antisense oligonucleotide reduced ERK1/2 activation, cell proliferation and enhanced the susceptibility of cells to Oxaliplatin-induced death. This is the first study showing up-regulation of IL-34 in CRC and suggesting a role for this cytokine in colon tumorigenesis.