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

Abstract

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-kappaB and IFN-beta luciferase reporter genes and the levels of two end products of TLR3 signaling, IFN-beta 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.

Proinsulinoma causing severe hypoglycemia in a patient with type 1 diabetes mellitus

“…The significance of this finding is unknown; however, TLR3 and Wnt-5a are coordinately expressed in certain tumor lines which have undergone malignant transformation [17,18] but not in benign tumors. Chronic inflammation within the pancreas is thought to contribute to the increased prevalence of pancreatic cancer in persons with T2DM [23,24] .…”

“…The Wingless (Wnt) family of secreted glycoproteins control early developmental processes including cellular migration, differentiation, and proliferation but are also involved in oncogenesis and tumor spread [16] . Recently, we demonstrated that high basal expression of TLR3 and Wnt5a are coordinately expressed in tumors that have undergone malignant transformation and their determination immunohistochemically might serve as a diagnostic marker [17,18] .…”

Dysregulation of secretion of CXC α-chemokine CXCL10 in papillary thyroid cancer: modulation by peroxisome proliferator-activated receptor-γ agonists

“…Furthermore, it has been shown recently that high basal levels of Toll-like receptor 3 (TLR3) and noncanonical WNT5a RNA are present in PTCs cell lines consistent with their overexpression and colocalization in PTC cells in vivo, and that the basally expressed TLR3 are functional in PTC cells, as evidenced by the ability of double-strand RNA (polyinosine-polycytidylic acid) to increase significantly the levels of the end product of TLR3 signaling CXCL10 (McCall et al 2007).…”

TLR-10 polymorphism and papillary thyroid cancer: one more SNP to consider?

“…This induces proinflammatory cytokine secretion (IL6 and IL1), antiapoptotic factors (Bcl-XL, cIAP1, ABL), as well as, pro-angiogenic factors expression (VEGF). High expression of TLR3 has been reported in a papillary thyroid cancer cell line which is consistent with its overexpression in human papillary thyroid cancer in vivo [5]. As one of the main mediator of lipopolysaccharide action, the lack or overexpression of TLR4 has also been associated with aggressive follicular thyroid cancers [6].…”