Chemerin acts via CMKLR1 and GPR1 to stimulate migration and invasion of gastric cancer cells: putative role of decreased TIMP-1 and TIMP-2

Abstract

The chemokine-like peptide, chemerin, stimulates chemotaxis in several cell types. In this study we examined the expression of putative chemerin receptors in gastric cancer and the action of chemerin on cancer cell migration and invasion. Immunohistochemical studies of gastric tumors identified expression of two putative receptors, chemokine-like receptor-1 (CMKLR1) and G-protein coupled receptor 1(GPR1), in cancer cells; there was also some expression in stromal myofibroblasts although generally at a lower intensity. The expression of both receptors was detected in a gastric cancer cell line, AGS; chemerin itself was expressed in cultured gastric cancer myofibroblasts but not AGS cells. Chemerin stimulated (a) morphological transformation of AGS cells characterized by extension of processes and cell scattering, (b) migration in scratch wound assays and (c) both migration and invasion in Boyden chamber chemotaxis assays. These responses were inhibited by two putative receptor antagonists CCX832 and α-NETA. Inhibition of receptor expression by siRNA selectively reduced CMKLR1 or GPR1 and inhibited the action of chemerin indicating that both receptors contributed to the functional response. Using a proteomic approach employing stable isotope dynamic labeling of secretomes (SIDLS) to selectively label secreted proteins, we identified down regulation of tissue inhibitors of metalloproteinease (TIMP)1 and TIMP2 in media in response to chemerin. When cells were treated with chemerin and TIMP1 or TIMP2 the migration response to chemerin was reduced. The data suggest a role for chemerin in promoting the invasion of gastric cancer cells via CMKLR1 and GPR1at least partly by reducing TIMP1 and TIMP2 expression. Chemerin receptor antagonists have potential in inhibiting gastric cancer progression.

Chemerin-156 is the Active Isoform in Human Hepatic Stellate Cells

“…In adipose tissues, GPR1 mRNA was highly abundant in the stromal vascular cell fraction, which is composed of fibroblasts, mesenchymal stem cells, endothelial cells, as well as smooth muscle cells and macrophages [ 8 , 9 ]. Chemerin is a well described chemoattractant and can act via both receptors to stimulate chemotaxis of immune or non-immune cells [ 1 , 10 , 11 , 12 ].…”

CMKLR1-targeting peptide tracers for PET/MR imaging of breast cancer

“…Increased CMKLR1 expression, chemerin-mediated tumor cell migration and invasion in ESCC were also found by Kumar et al [27]. Likewise, CMKLR1 has been implicated in neuroblastoma proliferation [28], hepatocellular carcinoma metastasis [29] and migration/invasion of gastric cancer [30]. CMKLR1 may therefore be a promising target for molecular imaging and targeted radionuclide therapy in overexpressing tumor entities.…”

“…Although known for its role in inflammation and metabolic regulation for many years, CMKLR1 and its chemokine-like ligand chemerin were only recently recognized as modulators of tumor proliferation and expansion. While other labs have reported overexpression and functional involvement of CMKLR1 in esophageal squamous cell carcinoma, hepatocellular carcinoma, neuroblastoma and gastric cancer [27-30], we have recently found CMKLR1 overexpression in breast cancer and pancreatic adenocarcinoma and have consequently developed two peptide analogs of chemerin for use in receptor-mediated tumor targeting (manuscript in preparation). These peptide analogs were based on chemerin-9, which has full agonistic activity towards the receptor CMKLR1 and corresponds to the C-terminal nine amino acids of processed chemerin [32].…”

Effect of ursodeoxycholic acid therapy due to pregnant intrahepatic cholestasis on chemerin and irisin levels

“…Kumar et al () as well as Shin and Pachynski () made interesting observations on the topic of the role and meaning of chemerin in the context of inflammatory bowel diseases. They determined that an increased concentration of chemerin in patients with disease remission, than in the group with an active form of enteritis.…”

“…A second of the assessed indicators was chemerin, which for the most part is secreted by adipocytes of adipose tissue, hepatocytes, thrombocytes and nephrons. It is secreted in the form of an inactive protein, which under the influence of proteolytic treatment is transformed into adipokine with specific biological activity(Yoshimura & Oppenheim, 2011) Kumar et al (2019). as well asShin and Pachynski (2018) made interesting observations on the topic of the role and meaning of chemerin in the context of inflammatory bowel diseases.…”