Cxcl14

Chemokines, a subgroup of cytokines, are small (size between 8 and 10 kDa), chemotactically active proteins (signal proteins). They are common in all vertebrates, some virus types and bacteria. In humans, about 50 chemokines are currently known. A strongly conserved structural feature of all chemokines is a fixed group of cysteine residues that is stabilized by 1 or 2 disulfide bridges. This key structural position in the molecule is responsible for its fixed 3-dimensional structure (see below chemokines).
In the CC-chemokines the cysteines follow each other directly, in the CXC-chemokines they are separated by 1 (see figure), in the CXXXC-chemokines by 3 other amino acids (see figure). Chemokines are produced and secreted by a large number of immune cells. They mediate their signals by means of specific chemokine receptors via G-proteins. The fact that chemokines and their receptors are not only expressed on inflammatory cells, but also by epithelial cells, mesenchymal cells, neurogenic cells, endothelial cells, and various tumor cell lines, suggests that they participate in numerous regulatory cell functions.

CXCL14, also known as C-X-C motif chemokine 14 or BRAK (= breast and kidney-expressed chemokine) is a small chemokine consisting of111 amino acids from the group of CXC chemokines. The highly conserved chemokine is encoded by the CXCL14 gene, which is located on chromosome 5 in humans.
CXCL14 binds with a high affinity to the chemokine receptor (see figure) CXCR4. This receptor belongs to the family of transmembrane, G-protein coupled chemokine receptors. CXCL14 competes at this receptor with the chemokine CXCL12 and blocks CXCL12-induced chemotaxis by inernalizing the receptor.

CXCL14 is physiologically expressed at high levels in normal tissues by fibroblasts. In contrast, the chemokine is reduced or completely absent in tumor cell lines.
CXCL14 acts chemotactically on monocytes, NK cells, but not on lymphocytes, dendritic cells, neutrophil granulocytes or macrophages. Monocytes are activated in the presence of prostate aglandin E2 (PEG2). In contrast, CXCL14 inhibits angiogenesis by blocking chemotaxis of endothelia.
The chemokine is thought to have a regulating effect on the homeostasis of monocytes-derived macrophages and to be less involved in inflammatory processes. Its exact function in different infections is not yet fully understood.
The CXCL14 gene is involved in the development and progression of colorectal cancer and acts directly as a tumor suppressor gene. The CXCL14 chemokine expression could become a valuable prognostic biomarker (the expression of CXCL14 is significantly reduced) in this tumor.
Also in Ewing's sarcoma, high expression of CXCL14 (and CXCR7) is associated with a positive correlation with respect to survival.
CXCL14 is massively downregulated in HPV-positive carcinomas. HPV-induced suppression of CXCL14 expression is associated with (virus-induced) DNA hypermethylation in the CXCL14 promoter.

1. Cicchini L et al(2016) Suppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL14 MBio pii: e00270-16.
2. Hara T et al (2014) CXCL14 antagonizes the CXCL12-CXCR4 signaling axis. Biomol Concepts 5:167-73.
3. Lin K et al (2014) Expression and effect of CXCL14 in colorectal carcinoma. Mol Med Rep 10:1561-1568.
4. Sand LG et al(2015) CXCL14, CXCR7 expression and CXCR4 splice variant ratio associate with survival and metastases in Ewing sarcoma patients. Eur J Cancer 51:2624-2633.
5. Sidahmed AM et al(2014) CXCL14 deficiency does not impact the outcome of influenza or Escherichia coli infections in mice. J Infect Dev Ctries 8:1301-1306.