The paramount role of cytokines and chemokines in papillary thyroid cancer: a review and experimental results
- 30 Downloads
Our study demonstrates that (C-X-C motif) ligand 9 and 11 (CXCL9, CXCL11) chemokines were absent basally in non-neoplastic thyroid (TFC) and papillary thyroid carcinoma (PTC) cells. Interferon (IFN)γ induced the chemokine secretion in TFC and PTC, while tumor necrosis factor (TNF)α induced it only in PTC. IFNγ+TNFα induced a synergistic chemokines release in PTC, and at a lower level in TFC. Peroxisome proliferator-activated receptor (PPAR)γ agonists suppressed dose-dependently IFNγ+TNFα-induced chemokine release in TFC, while stimulated it in PTC. PPARγ knocking down, by RNA interference technique in PTC cells, abolished the effect of PPARγ agonists on chemokines release. In PTC cells, PPARγ agonists reduced proliferation, and CXCL9 or CXCL11 (100 and 500 pg/mL) reduced proliferation and migration (P < 0.01, for all). In conclusion, in PTC cells: (a) IFNγ+TNFα induced a marked release of CXCL9 and CXCL11; (b) PPARγ agonists stimulated CXCL9 and CXCL11 secretion, while inhibited proliferation; (c) CXCL9 and CXCL11 inhibited proliferation and migration. The use of CXCL9 or CXCL11 as antineoplastic agents in PTC remains to be explored.
• IFNγ and IFNγ+TNFα induce dose-dependently CXCL9 (and less CXCL11) in PTC cells.
• Rosi and Pio dose-dependently inhibit the PTC cells proliferation.
• Rosi and Pio (at variance of normal TFC) stimulate CXCL9 or CXCL11 secretion.
• CXCL9 or CXCL11 induce a significant antiproliferative effect in PTC cells.
• Chemokines induced by IFNγ (CXCL9 or CXCL11) inhibit migration in PTC cells.
KeywordsCXCL9 CXCL11 Papillary thyroid cancer PPARγ CXCL10
We thank Dr. Michaela Francalanci for her contribution in the realization of siRNA studies.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Compliance with ethical standards
Conflict of Interests
The authors declare that they have no conflict of interest.
- 3.Suyama T, Furuya M, Nishiyama M, Kasuya Y, Kimura S, Ichikawa T, et al. Up-regulation of the interferon gamma (IFN-gamma)-inducible chemokines IFN-inducible T-cell alpha chemoattractant and monokine induced by IFN-gamma and of their receptor CXC receptor 3 in human renal cell carcinoma. Cancer. 2005;103:258–67.CrossRefGoogle Scholar
- 5.Melillo RM, Castellone MD, Guarino V, De Falco V, Cirafici AM, Salvatore G, et al. The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells. J Clin Invest. 2005;115:1068–81 (Retracted Article; Citation for this retraction: J Clin Invest 2016;126:1603).CrossRefGoogle Scholar
- 8.McCall KD, Harii N, Lewis CJ, Malgor R, Kim WB, Saji M, et al. High basal levels of functional toll-like receptor 3 (TLR3) and noncanonical Wnt5a are expressed in papillary thyroid cancer and are coordinately decreased by phenylmethimazole together with cell proliferation and migration. Endocrinology. 2007;148:4226–37.CrossRefGoogle Scholar
- 12.Antonelli A, Rotondi M, Fallahi P, Grosso M, Boni G, Ferrari SM, et al. Iodine-131 given for therapeutic purposes modulates differently interferon-gamma-inducible alpha-chemokine CXCL10 serum levels in patients with active graves’ disease or toxic nodular goiter. J Clin Endocrinol Metab. 2007;92:1485–90.CrossRefGoogle Scholar
- 13.Antonelli A, Ferrari SM, Fallahi P, Frascerra S, Santini E, Franceschini SS, et al. Monokine induced by interferon gamma (IFNgamma) (CXCL9) and IFNgamma inducible T-cell alpha-chemoattractant (CXCL11) involvement in Graves' disease and ophthalmopathy: modulation by peroxisome proliferator-activated receptor-gamma agonists. J Clin Endocrinol Metab. 2009;94:1803–9.CrossRefGoogle Scholar
- 27.Antonelli A, Ferrari SM, Fallahi P, Piaggi S, Paolicchi A, Franceschini SS, et al. Cytokines (interferon-γ and tumor necrosis factor-α)-induced nuclear factor-κB activation and chemokine (C-X-C motif) ligand 10 release in graves disease and ophthalmopathy are modulated by pioglitazone. Metabolism. 2011;60:277–83.CrossRefGoogle Scholar
- 28.Lombardi A, Cantini G, Piscitelli E, Gelmini S, Francalanci M, Mello T, et al. A new mechanism involving ERK contributes to rosiglitazone inhibition of tumor necrosis factor-alpha and interferon-gamma inflammatory effects in human endothelial cells. Arterioscler Thromb Vasc Biol. 2008;28:718–24.CrossRefGoogle Scholar
- 39.Schweppe RE, Klopper JP, Korch C, Pugazhenthi U, Benezra M, Knauf JA, et al. Deoxyribonucleic acid profiling analysis of 40 human thyroid cancer cell lines reveals cross-contamination resulting in cell line redundancy and misidentification. J Clin Endocrinol Metab. 2008;93:4331–41.CrossRefGoogle Scholar
- 42.Schaefer KL, Denevich S, Ma C, Cooley SR, Nakajima A, Wada K, et al. Intestinal antiinflammatory effects of thiazolidenedione peroxisome proliferator-activated receptor-gamma ligands on T helper type 1 chemokine regulation include nontranscriptional control mechanisms. Inflamm Bowel Dis. 2005;11:244–52.CrossRefGoogle Scholar