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

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.

• Authors: Eleonora Franzè, Vicenzo Dinallo, Angela Rizzo, Martina Di Giovangiulio, Gerolamo Bevivino, Carmine Stolfi, Flavio Caprioli, Alfredo Colantoni, Angela Ortenzi, Antonio Di Grazia, Giuseppe Sica, Pier Paolo Sileri, Piero Rossi, Giovanni Monteleone
• Journal: Oncotarget (Oncotarget) Vol. 9 Issue 3 Pg. 3432-3445 (01 09 2018) ISSN: 1949-2553 [Electronic] United States
• PMID: 29423057 (Publication Type: Journal Article)