title: Role of glutaminyl cyclases in thyroid carcinomas.
abstract: CCL2 is a chemokine known to recruit monocytes/macrophages to sites of inflammation. CCL2 is also associated with tumor progression in several cancer types. Recently, we showed that the N-terminus of CCL2 is modified to a pyroglutamate (pE)-residue by both glutaminyl cyclases (QC (QPCT)) and its isoenzyme (isoQC (QPCTL)). The pE-residue increases stability against N-terminal degradation by aminopeptidases. Here, we report an upregulation of QPCT expression in tissues of patients with thyroid carcinomas compared with goiter tissues, whereas QPCTL was not regulated. In thyroid carcinoma cell lines, QPCT gene expression correlates with the mRNA levels of its substrate CCL2. Both QPCT and CCL2 are regulated in a NF-κB-dependent pathway shown by stimulation with TNFa and IL1b as well as by inhibition with the IKK2 inhibitor and RNAi of p50. In the culture supernatant of thyroid carcinoma cells, equal amounts of pECCL2 and total CCL2 were detected by two ELISAs discriminating between total CCL2 and pECCL2, concluding that all CCL2 is secreted as pECCL2. Activation of the CCL2/CCR2 pathway by recombinant CCL2 increased tumor cell migration of FTC238 cells in scratch assays as well as thyroid carcinoma cell-derived CCL2-induced migration of monocytic THP1 cells. Suppression of CCL2 signaling by CCR2 antagonist, IKK2 inhibitor, and QPCT RNAi reduced FTC238 cell growth measured by WST8 proliferation assays. Our results reveal new evidence for a novel role of QC in thyroid carcinomas and provide an intriguing rationale for the use of QC inhibitors as a means of blocking pECCL2 formation and preventing thyroid cancer metastasis.
authors.affiliation: Probiodrug AG, Weinbergweg 22, Halle, Saale, Germany. astrid.kehlen@probiodrug.de
authors.forename: Astrid
authors.initials: A
authors.lastname: Kehlen
authors.forename: Monique
authors.initials: M
authors.lastname: Haegele
authors.forename: Katja
authors.initials: K
authors.lastname: Menge
authors.forename: Kathrin
authors.initials: K
authors.lastname: Gans
authors.forename: Uta-Dorothee
authors.initials: UD
authors.lastname: Immel
authors.forename: Cuong
authors.initials: C
authors.lastname: Hoang-Vu
authors.forename: Thomas
authors.initials: T
authors.lastname: Klonisch
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis; D004797:Enzyme-Linked Immunosorbent Assay; D006042:Goiter / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D007527:Isoenzymes; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013961:Thyroid Gland / Q000378:metabolism* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D018932:Chemokine CCL2; D007527:Isoenzymes; D016328:NF-kappa B; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase