Chemerin acts via CMKLR1 and GPR1 to stimulate migration and invasion of gastric cancer cells

Putative role of decreased TIMP-1 and TIMP-2

J. Dinesh Kumar, Iman Aolymat, L. Tiszlavicz, Zita Reisz, Hanan M. Garalla, Rob Beynon, Deborah Simpson, Graham J. Dockray, Andrea Varro

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)98-112
Number of pages15
JournalOncotarget
Volume10
Issue number2
Publication statusPublished - Jan 1 2019

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Chemokine Receptors
G-Protein-Coupled Receptors
Stomach Neoplasms
Myofibroblasts
Chemotaxis
Isotope Labeling
Neoplasms
Chemokines
Proteomics
Small Interfering RNA
Cell Movement
Stomach
Down-Regulation
Cell Line
Peptides
Wounds and Injuries
Proteins

Keywords

  • Chemerin
  • Gastric cancer
  • Myofibroblasts
  • Proteomic

ASJC Scopus subject areas

  • Oncology

Cite this

Dinesh Kumar, J., Aolymat, I., Tiszlavicz, L., Reisz, Z., Garalla, H. M., Beynon, R., ... Varro, A. (2019). Chemerin acts via CMKLR1 and GPR1 to stimulate migration and invasion of gastric cancer cells: Putative role of decreased TIMP-1 and TIMP-2. Oncotarget, 10(2), 98-112.

Chemerin acts via CMKLR1 and GPR1 to stimulate migration and invasion of gastric cancer cells : Putative role of decreased TIMP-1 and TIMP-2. / Dinesh Kumar, J.; Aolymat, Iman; Tiszlavicz, L.; Reisz, Zita; Garalla, Hanan M.; Beynon, Rob; Simpson, Deborah; Dockray, Graham J.; Varro, Andrea.

In: Oncotarget, Vol. 10, No. 2, 01.01.2019, p. 98-112.

Research output: Contribution to journalArticle

Dinesh Kumar, J, Aolymat, I, Tiszlavicz, L, Reisz, Z, Garalla, HM, Beynon, R, Simpson, D, Dockray, GJ & Varro, A 2019, 'Chemerin acts via CMKLR1 and GPR1 to stimulate migration and invasion of gastric cancer cells: Putative role of decreased TIMP-1 and TIMP-2', Oncotarget, vol. 10, no. 2, pp. 98-112.
Dinesh Kumar, J. ; Aolymat, Iman ; Tiszlavicz, L. ; Reisz, Zita ; Garalla, Hanan M. ; Beynon, Rob ; Simpson, Deborah ; Dockray, Graham J. ; Varro, Andrea. / Chemerin acts via CMKLR1 and GPR1 to stimulate migration and invasion of gastric cancer cells : Putative role of decreased TIMP-1 and TIMP-2. In: Oncotarget. 2019 ; Vol. 10, No. 2. pp. 98-112.
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