Dysregulation of secretion of CXC alpha-chemokine CXCL10 in papillary thyroid cancer: modulation by peroxisome proliferator-activated receptor-gamma agonists.
In papillary thyroid carcinomas (PTCs), oncogenes activate a transcriptional program including the upregulation of CXCL10 chemokine, which stimulates proliferation and invasion. Furthermore, peroxisome proliferator-activated receptor-gamma (PPARgamma) activators thiazolidinediones (TZDs) modulate CXCL10 secretion in normal thyroid follicular cells (TFC), and inhibit PTC growth. Until now, no study has evaluated the effect of cytokines on CXCL10 secretion in PTCs, nor the effect of PPARgamma activation. The combined effects of interferon gamma (IFNgamma) and tumor necrosis factor alpha (TNFalpha) stimulation on CXCL10 secretion in primary cells from PTCs and TFC were tested. Furthermore, the effect of PPARgamma activation by TZDs, on CXCL10 secretion and proliferation in these cell types was studied. In primary cultures of TFC and PTCs CXCL10 production was absent under basal conditions; a similar dose-dependent secretion of CXCL10 was induced by IFNgamma in both cell types. TNFalpha alone induced a slight but significant CXCL10 secretion only in PTCs. The stimulation with IFNgamma+TNFalpha induced a synergistic CXCL10 release in both cell types; however, a secretion more than ten times higher was induced in PTCs. Treatment of TFC with TZDs dose-dependently suppressed IFNgamma+TNFalpha-induced CXCL10 release, while TZDs stimulated CXCL10 secretion in PTCs. A significant antiproliferative effect by TZDs was observed only in PTCs. In conclusion, a dysregulation of CXCL10 secretion has been shown in PTCs. In fact, a CXCL10 secretion more than ten times higher has been induced by IFNgamma+TNFalpha in PTCs with respect to TFC. Moreover, TZDs inhibited CXCL10 secretion in TFC and stimulated it in PTCs. The effect of TZDs on CXCL10 was unrelated to the significant antiproliferative effect in PTCs.
Antonelli
Alessandro
A
Department of Internal Medicine, School of Medicine, University of Pisa, Pisa, Italy. a.antonelli@med.unipi.it
Ferrari
Silvia Martina
SM
Fallahi
Poupak
P
Frascerra
Silvia
S
Piaggi
Simona
S
Gelmini
Stefania
S
Lupi
Cristiana
C
Minuto
Michele
M
Berti
Piero
P
Benvenga
Salvatore
S
Basolo
Fulvio
F
Orlando
Claudio
C
Miccoli
Paolo
P
D017209:Apoptosis / Q000187:drug effects; D002291:Carcinoma, Papillary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000494:pharmacology*; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D054357:Chemokine CXCL10; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma