Integrative genomic analyses of a novel cytokine, interleukin-34 and its potential role in cancer prediction

Abstract

Interleukin-34 (IL-34) is a novel cytokine, which is composed of 222 amino acids and forms homodimers. It binds to the macrophage colony-stimulating factor (M-CSF) receptor and plays an important role in innate immunity and inflammatory processes. In the present study, we identified the completed IL-34 gene in 25 various mammalian genomes and found that IL-34 existed in all types of vertebrates, including fish, amphibians, birds and mammals. These species have a similar 7 exon/6 intron gene organization. The phylogenetic tree indicated that the IL-34 gene from the primate lineage, rodent lineage and teleost lineage form a species-specific cluster. It was found mammalian that IL-34 was under positive selection pressure with the identified positively selected site, 196Val. Fifty-five functionally relevant single nucleotide polymorphisms (SNPs), including 32 SNPs causing missense mutations, 3 exonic splicing enhancer SNPs and 20 SNPs causing nonsense mutations were identified from 2,141 available SNPs in the human IL-34 gene. IL-34 was expressed in various types of cancer, including blood, brain, breast, colorectal, eye, head and neck, lung, ovarian and skin cancer. A total of 5 out of 40 tests (1 blood cancer, 1 brain cancer, 1 colorectal cancer and 2 lung cancer) revealed an association between IL-34 gene expression and cancer prognosis. It was found that the association between the expression of IL-34 and cancer prognosis varied in different types of cancer, even in the same types of cancer from different databases. This suggests that the function of IL-34 in these tumors may be multidimensional. The upstream transcription factor 1 (USF1), regulatory factor X-1 (RFX1), the Sp1 transcription factor 1, POU class 3 homeobox 2 (POU3F2) and forkhead box L1 (FOXL1) regulatory transcription factor binding sites were identified in the IL-34 gene upstream (promoter) region, which may be involved in the effects of IL-34 in tumors.

Interleukin‐34 mediated by hepatitis B virus X protein via CCAAT/enhancer‐binding protein α contributes to the proliferation and migration of hepatoma cells

“…Importantly, the increased IL‐34 was associated with liver inflammation and fibrosis in HBV infection, and the results were consistent with the phenomenon observed in non‐alcoholic fatty liver disease and chronic hepatitis C . Besides these, IL‐34 is shown to increase in different tumour cells, and related to the prognosis of various cancers. In addition, Zhou S et al showed that the upregulation of IL‐34 contributed the development of HCC .…”

Emerging roles of IL-34 in health and disease

“…Regarding IL-34, emerging data also demonstrate its correlation with poor prognosis in several cancers, such as osteosarcoma and lung and breast cancer ( Fig. 3; Baghdadi et al, 2018;Wang et al, 2015). Expressed by various types of cancer cells and further induced upon chemotherapy treatment (Baghdadi et al, 2016;Baud'Huin et al, 2010;Cioce et al, 2014;Franzè et al, 2017;Wang et al, 2015), IL-34 binds to CSF-1R on mononuclear phagocytes, which play distinct roles during different stages of tumor progression (Baud'Huin et al, 2010;Noy and Pollard, 2014;Ségaliny et al, 2015c;Zins et al, 2018).…”

Integrative genomic analysis of interleukin-36RN and its prognostic value in cancer

“…Ensembl (http://www.ensembl.org/index.html) and the NCBI's Database of SNPs (http://www.ncbi.nlm.nih. gov/snp/) were used to obtain functionally relevant SNPs of the human IL-36RN gene as previously described (24,27,28). The SNPs that could disrupt exonic splicing enhancer (ESE)/exonic splicing silencer (ESS) motifs or cause a missense mutation were identified.…”