Oncotarget

Research Papers:

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

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 and Giovanni Monteleone _

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Oncotarget. 2018; 9:3432-3445. https://doi.org/10.18632/oncotarget.23289

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Abstract

Eleonora Franzè1, Vicenzo Dinallo1, Angela Rizzo1, Martina Di Giovangiulio1, Gerolamo Bevivino1, Carmine Stolfi1, Flavio Caprioli2, Alfredo Colantoni1, Angela Ortenzi1, Antonio Di Grazia1, Giuseppe Sica3, Pier Paolo Sileri3, Piero Rossi3 and Giovanni Monteleone1

1Department of Systems Medicine, University of Rome “TOR VERGATA”, Rome, Italy

2Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

3Department of Surgery, University “TOR VERGATA” of Rome, Rome, Italy

Correspondence to:

Giovanni Monteleone, email: [email protected]

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.


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