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  • For several years CXCL had been classified


    For several years, CXCL17 had been classified as an orphan chemokine, until Maravillas-Montero et al. claimed that orphan G-coupled protein receptor GPR35 is the receptor of CXCL17 [15], [16]. However, no following research has been produced to further explore the function of the CXCL17-CXCR8 (GPR35) axis in cancer after this breakthrough. Therefore, the aim of our study is to clarify the function of this axis in breast cancer. Firstly, we explore the expression pattern of these two proteins. Secondly, we identify their association with clinicopathology and the survival of patients. Finally, we test their function in breast cancer Pimozide in vitro and in vivo.
    Materials and methods
    Discussion The third part of our study reported the function of CXCL17 in breast cancer cell lines both in vitro and in vivo. The transwell assay and confluence of cell monitoring indicated that knockdown of CXCL17 could inhibit breast cancer cell migration and proliferation in vitro. The orthotopic xenograft model in BALB/c mice demonstrated that overexpression of mice CXCL17 in 4T1 cells increased tumor formation and metastasis. This indicated that CXCL17 could promote breast cancer cell proliferation and migration in vivo. Our results agree with the findings of previous studies, namely that (1) CXCL17 can accelerate NIH3T3 and SW620 cell transplantation tumor formation in SCID mice [6]. (2) CXCL17 can promote proliferation of SMMC7721 hepatoma carcinoma cells in vitro and in vivo[18]. (3) Ectopic expression of CXCL17 in colon cancer cells are associated with poor outcome [11]. Therefore, we conclude that CXCL17 may act as an oncogene in many solid tumors including breast cancer. To our understanding, this is the first comprehensive report detailing breast cancer progression in relation to the CXCL17-CXCR8 (GPR35) biological axis. However, the function of CXCR8 (GPR35) is still ambiguous. While its expression in breast cancer is associated with advanced histological grade and a higher proliferation rate, breast cancer outcomes remain unclear. CXCL17 can activate CXCR8 (GPR35), although its expression and function was found to be different in breast cancer epithelial cells. Accordingly, we suspect with reasonable confidence that CXCR8 (GPR35), the receptor of CXCL17, may function in other cell types besides breast cancer cells, such as immunocytes, endothelial and stromal cells, and interact with CXCL17 through paracrine or other mechanisms. To verify this assumption, further research is required.
    Conflicts of interest
    Introduction The kynurenine (KYN) pathway of tryptophan (TRP) degradation is the major catabolic pathway for this essential amino acid. It is responsible for metabolizing up to 95% of free TRP and generates a group of metabolites collectively referred to as “kynurenines” with NAD+ as the end product (Cervenka et al., 2017). KYN and its metabolites participate in several physiological and pathophysiological processes, most notably in the CNS, where they are involved in the etiology of several mental health disorders such as depression and schizophrenia (Schwarcz et al., 2012). The actions of KYNs in peripheral tissues are less well established, but some have been shown to be strong modulators of immune cell function (Mándi and Vécsei, 2012, Stone et al., 2013). We have previously shown that exercised skeletal muscle can increase the conversion of KYN to kynurenic acid (KYNA) (Agudelo et al., 2014), a metabolite that cannot cross the blood-brain barrier (Fukui et al., 1991). Activation of this pathway in skeletal muscle is dependent on the transcriptional coactivator Pgc-1α1 (Correia et al., 2015) and protects the brain from stress-induced KYN accumulation and associated deleterious effects (i.e., neuroinflammation and changes in synaptic plasticity associated with depression) (Agudelo et al., 2014). Since KYNA is not transported across the blood-brain barrier it is locally produced in the CNS from KYN (Müller and Schwarz, 2007) by KYN aminotransferases (KATs). Actions of KYNA in the CNS are related to its activity as an antagonist for N-methyl-D-aspartate (NMDA) and cholinergic α7 nicotinic receptors (Vécsei et al., 2013), and agonist for the recently de-orphanized G protein-coupled receptor (GPCR) 35 (Gpr35) (Divorty et al., 2015). Interestingly, we and others have shown that even in the absence of a stress challenge, endurance exercise training is sufficient to activate skeletal muscle KYN to KYNA conversion, resulting in considerably elevated circulating KYNA levels (Agudelo et al., 2014, Lewis et al., 2010, Schlittler et al., 2016). In the periphery, high levels of KYNA have been observed in patients with inflammatory bowel disease and other pathologies of the gastrointestinal tract (GIT) (Forrest et al., 2002). Finally, KYNA has been reported to have anti-inflammatory properties and to modulate cytokine release from invariant natural killer T (iNKT) cells through Gpr35 activation (Fallarini et al., 2010).