Iodine regulates G2/M progression induced by CCL21/CCR7 interaction in primary cultures of papillary thyroid cancer cells with RET/PTC expression

Mol Med Rep. 2016 Oct;14(4):3941-6. doi: 10.3892/mmr.2016.5686. Epub 2016 Aug 29.

Abstract

Treatment with high iodine concentrations can delay oncogenic activation effects, reduce cell growth and return thyroid-specific gene and protein expression levels to normal. During rearranged during transfection (RET)/papillary thyroid carcinoma (PTC) 3 activation, excess iodine can act as a protective agent in thyroid follicular cells. The chemokine receptor CCR7 serves a critical role in lymphocyte trafficking into and within lymph nodes, the preferential metastatic site for PTC. However, the potential associations between chemokine (C‑C motif) ligand 21 (CCL21)/C‑C chemokine receptor type 7 (CCR7) interaction and iodine concentrations in primary cultures of PTC with RET/PTC expression remain unclear. Proliferation assays of primary cultures of PTC cells with RET/PTC1 and RET/PTC3 expression indicated that CCR7 activation by its specific ligand, CCL21, was associated with significantly increased cell proliferation. Flow cytometry data indicated that CCL21/CCR7 interaction significantly increased the fraction of cells in the G2/M phase of the cell cycle. Western blotting indicated that CCL21/CCR7 interaction significantly upregulated cyclin A, cyclin B1 and cyclin‑dependent kinase 1 (CDK1) expression. Western blotting determined that CCL21/CCR7 interaction significantly enhanced the levels of phosphorylated extracellular signal‑regulated kinase (P‑ERK). Co-immunoprecipitation confirmed that there was interaction between P‑ERK and cyclin A, cyclin B1 or CDK1, particularly in the presence of CCL21. Sodium iodide (NaI, 10-5 M) significantly abolished the effects of exogenous CCL21. These results suggest that CCL21/CCR7 interaction contributes to G2/M progression of RET/PTC‑expressing cells via the ERK pathway in association with 10‑5 M NaI.

MeSH terms

  • Adult
  • CDC2 Protein Kinase
  • Carcinoma / genetics
  • Carcinoma / metabolism*
  • Carcinoma / pathology*
  • Carcinoma, Papillary
  • Cell Division*
  • Cell Proliferation
  • Chemokine CCL21 / metabolism*
  • Chromosomes, Human, Pair 10 / genetics
  • Cyclin A / metabolism
  • Cyclin B / metabolism
  • Cyclin-Dependent Kinases / metabolism
  • Female
  • G2 Phase*
  • Gene Rearrangement
  • Humans
  • Iodine / metabolism*
  • MAP Kinase Signaling System
  • Male
  • Middle Aged
  • Protein Interaction Maps
  • Proto-Oncogenes
  • Receptors, CCR7 / metabolism*
  • Thyroid Cancer, Papillary
  • Thyroid Gland / metabolism
  • Thyroid Gland / pathology*
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / metabolism*
  • Thyroid Neoplasms / pathology*
  • Tumor Cells, Cultured

Substances

  • CCL21 protein, human
  • CCR7 protein, human
  • Chemokine CCL21
  • Cyclin A
  • Cyclin B
  • Receptors, CCR7
  • Iodine
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • Cyclin-Dependent Kinases