RAGE Mediates the Pro-Migratory Response of Extracellular S100A4 in Human Thyroid Cancer Cells.
BACKGROUND
Expression of the small calcium-binding protein S100A4 is associated with poor prognosis in patients with thyroid cancer (TC). The authors have previously shown that S100A4 is a target for relaxin and insulin-like peptide 3 signaling in TC cells and that S100A4 is secreted from human TC cells. Although the pro-migratory role of intracellular S100A4 in binding to non-muscle myosin is well known, this study investigated here whether extracellular S100A4 contributes to TC migration.


METHODS
Human cell lines of follicular, papillary, and undifferentiated thyroid cancer, primary patient TC cells, and TC tissues were utilized to discover the presence of the receptor of advanced glycation end products (RAGE) in TC cells and TC tissues. Fluorescence imaging, protein pull-down assays, Western blot, siRNA protein silencing, small GTPase inhibitors, cell proliferation, and cell migration assays were used to investigate the interaction of extracellular S100A4 with RAGE in promoting a TC migratory response.


RESULTS
It was demonstrated that RAGE served as receptor for extracellular S100A4 mediating cell migration in TC cells. The RAGE-mediated increase in cell migration was dependent on the intracellular RAGE signaling partner diaphanous-1 (Dia-1) and involved the activation of the small GTPases Cdc42 and RhoA. Although extracellular S100A4 consistently activated ERK signaling in TC cells, it was shown that ERK signaling was not mediated by RAGE and not essential for the migratory response in TC cells.


CONCLUSIONS
The data have identified the RAGE/Dia-1 signaling system as a mediator for the pro-migratory response of extracellular S100A4 in human TC. Thus, therapeutic targeting of the RAGE/Dia-1/small GTPases signaling may successfully reduce local invasion and metastasis in TC.
1 Department of Human Anatomy and Cell Science, University of Manitoba , Winnipeg, Canada .
Manoj Reddy
MR
Medapati
Mathias
M
Dahlmann
Saeid
S
Ghavami
Kumar Alok
KA
Pathak
Lydia
L
Lucman
Thomas
T
Klonisch
Cuong
C
Hoang-Vu
Ulrike
U
Stein
Sabine
S
Hombach-Klonisch
D018263:Adenocarcinoma, Follicular; D002291:Carcinoma, Papillary / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D011379:Prognosis; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C077591:S100A4 protein, human; D020764:cdc42 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein