Cell cycle dependent expression of the CCK2 receptor by gastrointestinal myofibroblasts

putative role in determining cell migration

Akos Varga, Jothi Dinesh Kumar, Alec W.M. Simpson, Steven Dodd, Peter Hegyi, Graham J. Dockray, A. Varró

Research output: Contribution to journalArticle

Abstract

The well-known action of the gastric hormone gastrin in stimulating gastric acid secretion is mediated by activation of cholecystokinin-2 receptors (CCK2R). The latter are expressed by a variety of cell types suggesting that gastrin is implicated in multiple functions. During wound healing in the stomach CCK2R may be expressed by myofibroblasts. We have now characterized CCK2R expression in cultured myofibroblasts. Immunocytochemistry showed that a relatively small proportion (1-6%) of myofibroblasts expressed the receptor regardless of the region of the gut from which they were derived, or whether from cancer or control tissue. Activation of CCK2R by human heptadecapeptide gastrin (hG17) increased intracellular calcium concentrations in a small subset of myofibroblasts indicating the presence of a functional receptor. Unexpectedly, we found over 80% of cells expressing CCK2R were also labeled with 5-ethynyl-2'-deoxyuridine (EdU) which is incorporated into DNA during S-phase of the cell cycle. hG17 did not stimulate EdU incorporation but increased migration of both EdU-labeled and unlabelled myofibroblasts; the migratory response was inhibited by a CCK2R antagonist and by an inhibitor of IGF receptor tyrosine kinase; hG17 also increased IGF-2 transcript abundance. The data suggest myofibroblasts express CCK2R in a restricted period of the cell cycle during S-phase, and that gastrin accelerates migration of these cells; it also stimulates migration of adjacent cells probably through paracrine release of IGF. Together with previous findings, the results raise the prospect that gastrin controls the position of dividing myofibroblasts which may be relevant in wound healing and cancer progression in the gastrointestinal tract.

Original languageEnglish
JournalPhysiological Reports
Volume5
Issue number19
DOIs
Publication statusPublished - Oct 1 2017

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Cholecystokinin B Receptor
Myofibroblasts
Cell Movement
Cell Cycle
Gastrins
Deoxyuridine
S Phase
Wound Healing
Stomach
Gastrin-Secreting Cells
Insulin-Like Growth Factor II
Gastric Acid
Receptor Protein-Tyrosine Kinases
Gastrointestinal Tract
Neoplasms
Immunohistochemistry
Hormones
Calcium
DNA

Keywords

  • CCK2R
  • cell cycle
  • gastrin
  • migration
  • myofibroblasts

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Cell cycle dependent expression of the CCK2 receptor by gastrointestinal myofibroblasts : putative role in determining cell migration. / Varga, Akos; Kumar, Jothi Dinesh; Simpson, Alec W.M.; Dodd, Steven; Hegyi, Peter; Dockray, Graham J.; Varró, A.

In: Physiological Reports, Vol. 5, No. 19, 01.10.2017.

Research output: Contribution to journalArticle

Varga, Akos ; Kumar, Jothi Dinesh ; Simpson, Alec W.M. ; Dodd, Steven ; Hegyi, Peter ; Dockray, Graham J. ; Varró, A. / Cell cycle dependent expression of the CCK2 receptor by gastrointestinal myofibroblasts : putative role in determining cell migration. In: Physiological Reports. 2017 ; Vol. 5, No. 19.
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abstract = "The well-known action of the gastric hormone gastrin in stimulating gastric acid secretion is mediated by activation of cholecystokinin-2 receptors (CCK2R). The latter are expressed by a variety of cell types suggesting that gastrin is implicated in multiple functions. During wound healing in the stomach CCK2R may be expressed by myofibroblasts. We have now characterized CCK2R expression in cultured myofibroblasts. Immunocytochemistry showed that a relatively small proportion (1-6{\%}) of myofibroblasts expressed the receptor regardless of the region of the gut from which they were derived, or whether from cancer or control tissue. Activation of CCK2R by human heptadecapeptide gastrin (hG17) increased intracellular calcium concentrations in a small subset of myofibroblasts indicating the presence of a functional receptor. Unexpectedly, we found over 80{\%} of cells expressing CCK2R were also labeled with 5-ethynyl-2'-deoxyuridine (EdU) which is incorporated into DNA during S-phase of the cell cycle. hG17 did not stimulate EdU incorporation but increased migration of both EdU-labeled and unlabelled myofibroblasts; the migratory response was inhibited by a CCK2R antagonist and by an inhibitor of IGF receptor tyrosine kinase; hG17 also increased IGF-2 transcript abundance. The data suggest myofibroblasts express CCK2R in a restricted period of the cell cycle during S-phase, and that gastrin accelerates migration of these cells; it also stimulates migration of adjacent cells probably through paracrine release of IGF. Together with previous findings, the results raise the prospect that gastrin controls the position of dividing myofibroblasts which may be relevant in wound healing and cancer progression in the gastrointestinal tract.",
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