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Submitted on April 9, 2007
Accepted on May 16, 2007
Edison Biotechnology Institute and College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA, The Ohio State University, Arthur G. James Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210, USA, The Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, The Department of Hematology, University of Washington, Seattle, WA 98195, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Korea
* To whom correspondence should be addressed. E-mail: KOHNL{at}ohiou.edu.
High basal levels of TLR3 and Wnt5a RNA are present in papillary thyroid carcinoma (PTC) cell lines consistent with their over-expression and co-localization in PTC cells in vivo. This is not the case in thyrocytes from normal tissue and in follicular (FC) or anaplastic (AC) carcinoma cells or tissues. The basally expressed TLR3 are functional in PTC cells as evidenced by the ability of double strand RNA (Poly I:C) to significantly increase the activity of transfected NF-
B and IFN-
luciferase reporter genes and the levels of two end products of TLR3 signaling, IFN- and CXCL10. Phenylmethimazole (C10), a drug which decreases TLR3 expression and signaling in FRTL-5 thyrocytes, decreases TLR3 levels and signaling in PTC cells in a concentration dependent manner. C10 also decreased Wnt5a RNA levels coordinate with decreases in TLR3. E-cadherin RNA levels, whose suppression may be associated with high Wnt5a, increased with C10 treatment. C10 simultaneously decreased PTC proliferation and cell migration, but had no effect on the growth and migration of FC, AC, or FRTL-5 cells. C10 decreases high basal phosphorylation of Tyr705 and Ser727 on Stat3 in PTC cells and inhibits IL-6-induced Stat3 phosphorylation. IL-6-induced Stat3 phosphorylation is important both in up-regulating Wnt5a levels and in cell growth. In sum, high Wnt5a levels in PTC cells may be related to high TLR3 levels and signaling; and the ability of phenylmethimazole (C10) to decrease growth and migration of PTC cells may be related to its suppressive effect on TLR3 and Wnt5a signaling, particularly Stat3 activation.
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