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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

Edison Biotechnology Institute and College of Osteopathic Medicine (K.D.M., N.H., C.J.L., R.M., W.B.K., L.D.K.), Ohio University, Athens, Ohio 45701; The Ohio State University, Arthur G. James Cancer Center and Richard J. Solove Research Institute (M.S.), Columbus, Ohio 43210; The Howard Hughes Medical Institute (A.D.K., R.T.M.) and Department of Hematology (A.D.K.), University of Washington, Seattle, Washington 98195; and Department of Internal Medicine (W.B.K.), Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Korea

Address all correspondence and requests for reprints to: Leonard D. Kohn, Konneker Research Building, Room 077, The Ridges, Building 25, Ohio University, Athens, Ohio 45701. 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 overexpression and colocalization in PTC cells in vivo. This is not the case in thyrocytes from normal tissue and in follicular carcinoma (FC) or anaplastic carcinoma (AC) cells or tissues. The basally expressed TLR3 are functional in PTC cells as evidenced by the ability of double-strand RNA (polyinosine-polycytidylic acid) to significantly increase the activity of transfected NF-B and IFN-ß luciferase reporter genes and the levels of two end products of TLR3 signaling, IFN-ß and CXCL10. Phenylmethimazole (C10), a drug that 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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