The Wnt/-catenin signaling pathway is involved in the normal development of

The Wnt/-catenin signaling pathway is involved in the normal development of thyroid gland, but its disregulation provokes the appearance of several types of cancers, including papillary thyroid carcinomas (PTC) which are the most common thyroid tumours. Practical promoter studies and ChIP analysis showed the Wnt/-catenin pathway exerts its effect by means of the binding of -catenin to TCF/LEF transcription factors on the level of an active TCF/LEF response element at [?798, ?792 bp] in TTF-1 promoter. In conclusion, we shown that the Wnt/-catenin pathway is definitely a direct and ahead driver of the TTF-1 manifestation. The localization of TCF-4 and TTF-1 in the same area of PTC cells might be of medical relevance, and justifies further examination of these factors in the papillary thyroid cancers follow-up. Intro Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy representing about 80% of all thyroid cancers [1]. Treatment of PTC is based on total thyroidectomy and radioiodine therapy [2]. The gold-standard method in the follow-up of individuals after surgery/radioiodine is based on monitoring of serum thyroglobulin (Tg) levels, which showed a higher level of sensitivity than cytology for the detection of cervical lymph node metastasis [3]. However, the thyroid specific transcription element TTF-1 regulates Tg manifestation by binding to GDC-0941 its promoter [4]. Consequently, TTF-1 is considered with Tg as the most important markers for follicular cells [5], [6]. The transcriptional element TTF-1 (also known as NKX2-1, T/EBP or TITF-1) is commonly expressed in the thyroid gland, lung and central nervous system [7]. It is considered as a marker of differentiation in thyroid and lung carcinoma [8] and has been widely used to discern the primary site of thyroid and lung tumour source in individuals with metastatic disease [9], [10], [11], [12]. In the thyroid gland, TTF-1 is definitely expressed in the GDC-0941 follicular cells and, together with GDC-0941 Pax8, controls the manifestation of Tg, thyroperoxydase (TPO), thyrotropin receptor (TSH), the sodium/iodide symporter (NIS) and calcitonin and major histocompatibility complex class I genes. As a result, the combination of these two factors plays a role in the manifestation of the thyroid-specific phenotype. mRNA is definitely recognized in papillary carcinomas (PTC) but not in anaplastic carcinomas; consequently TTF-1 is considered as a marker to distinguish between these two forms of thyroid neoplasms [13], [14]. Concerning the prognosis, TTF-1 manifestation may be improved in PTC with aggressive medical program [15]. The Wnt signaling pathway is a complex network of proteins explained to be involved in the control of thyrocyte proliferation [16] and to play a pivotal part in thyroid malignancy development [16]. In the absence of Wnt transmission, -catenin is definitely targeted for degradation in the proteasome. In the presence of Wnt ligands, the Frizzled receptor is definitely activated, leading to the repression of GSK3 and consequently to the build up of -catenin and its translocation to the nucleus [17]. There, -catenin forms a complex with the nuclear transcriptional regulator T-cell element/lymphoid enhancer element (TCF/LEF), to promote the manifestation of Wnt target genes [17]. For good examples in normal thyroid cells, Wnt-1 ligand enhances cell growth of GDC-0941 differentiated thyroid cell and regulates thyroperoxidase gene, a critical enzyme for thyroid hormone synthesis in thyrocytes [18] and GSK3 are tightly implicated in the thyrocytes activation [19]. Moreover, aberrant GDC-0941 activation of the Wnt signaling pathway may be a common denominator for the development of tumours [20] and strongly involved in thyroid tumorigenesis [21]. It was reported a dominating part of Wnt/-catenin signaling relative to the TSH/PKA/CREB pathway in the proliferation of normal and neoplastic thyrocytes [22]. Also, aberrant -catenin manifestation or localisation are often described to be associated with the more aggressive behaviour in PTCs [22]C[23] and many -catenin target genes have been shown to play an important part in cancer progression including and homeodomain-containing genes [24], [25], [26], [27], [28]. Furthermore, it has also been suggested that -catenin may play a direct part in the dedifferentiation of the late-stage disease of PTC [16], [29]. The part of Wnt/-catenin signaling in TTF-1 regulation remains unclear. The aim of this study is to investigate whether the Wnt/-catenin pathway could regulate TTF-1 expression in a papillary thyroid carcinoma model and to examine the mechanism(s) involved in this regulation. We show herein that Wnt/-catenin pathway is usually a direct driver of TTF-1 expression. Results The major components of the Wnt/-catenin signaling pathway and TTF-1 are co-expressed in the TPC-1 cell line and papillary thyroid carcinomas We investigated by real-time PCR Rabbit Polyclonal to TPH2 (phospho-Ser19) the relative expression in the TPC-1 cell line of TTF-1 as well as the major components.