TSH Receptor and Thyroid-Specific Gene Expression in Human Skin

Experimental evidence suggests that in autoimmune thyroid diseases (AITDs) the skin is a target of autoantibodies against thyroid-specific antigens; however, the role of these autoantibodies in skin alterations remains unclear. To gain insight into the function of nominally thyroid-specific genes in skin, we analyzed the expression of thyroid-stimulating hormone–receptor (TSH-R), thyroglobulin (Tg), sodium iodide symporter (NIS), and thyroperoxidase (TPO) genes in normal human skin biopsies and cultured primary keratinocytes and dermal fibroblasts. The results revealed the presence of all the transcripts in skin biopsies. However, in keratinocytes and fibroblasts, only TSH-R messenger RNA was always detected. Western blot and immunohistochemical analyses of skin specimens confirmed the presence of TSH-R protein in keratinocytes and fibroblasts. Moreover, TSH treatment induced the proliferation of cultured keratinocytes and fibroblasts and increased keratinocyte intracellular cAMP. Finally, affinity-purified IgGs from serum of patients affected by Graves’ disease, but not by chronic lymphocytic thyroiditis, stimulated cAMP accumulation in cultured keratinocytes, as well as their proliferation. In conclusion, the expression of thyroid-specific genes in cultured keratinocytes and fibroblasts and the mitogenic effects of TSH and IgGs on these cells support the concept that autoantibodies against thyroid-specific antigens may contribute to cutaneous symptoms in AITDs.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://network.nature.com/group/jidclu

Transforming acidic coiled-coil 3 and Aurora-A interact in human thyrocytes and their expression is deregulated in thyroid cancer tissues

Aurora-A kinase has recently been shown to be deregulated in thyroid cancer cells and tissues. Among the Aurora-A substrates identified, transforming acidic coiled-coil (TACC3), a member of the TACC family, plays an important role in cell cycle progression and alterations of its expression occur in different cancer tissues. In this study, we demonstrated the expression of the TACC3 gene in normal human thyroid cells (HTU5), and its modulation at both mRNA and protein levels during cell cycle. Its expression was found, with respect to HTU5 cells, unchanged in cells derived from a benign thyroid follicular tumor (HTU42), and significantly reduced in cell lines derived from follicular (FTC-133), papillary (B-CPAP), and anaplastic thyroid carcinomas (CAL-62 and 8305C). Moreover, in 16 differentiated thyroid cancer tissues, TACC3 mRNA levels were found, with respect to normal matched tissues, reduced by twofold in 56% of cases and increased by twofold in 44% of cases. In the same tissues, a correlation between the expression of the TACC3 and Aurora-A mRNAs was observed. TACC3 and Aurora-A interact in vivo in thyroid cells and both proteins localized onto the mitotic structure of thyroid cells. Finally, TACC3 localization on spindle microtubule was no more observed following the inhibition of Aurora kinase activity by VX-680. We propose that Aurora-A and TACC3 interaction is important to control the mitotic spindle organization required for proper chromosome segregation

Thyroid autoantibodies and breast cancer

Dear Editor We read with interest the recent article by Shi and colleagues (2014) reporting a meta-analysis on the relationship between thyroid hormones, thyroid autoantibodies and breast cancer (BC). In the paper, the authors analyzed eight different studies, including 4,189 participants, and concluded that serum levels of free-triiodothyronine, thyroperoxidase and thyroglobulin autoantibodies are higher in patients affected by BC, compared with the control group. These findings are in agreement with the meta-analysis reported by Hardefeldt and colleagues, showing an increased risk of BC in patients with autoimmune thyroid disease, and with a recent article by our group in which the prevalence of BC in 3,921 female patients affected by both benign and malignant thyroid diseases was evaluated (Hardefeldt et al., 2012; Prinzi et al., 2014). In the latter, we showed that the prevalence of BC in patients affected by thyroid disease, as a whole, was significantly higher, compared to the general population (OR 3.3). Moreover, the age-matched analysis showed that the risk of BC was higher in younger patients (0–44 yr, OR 15.2), to decline with the increasing age. In the same study, when patients were dichotomized based on the presence or the absence of thyroglobulin and/or thyroperoxidase autoantibodies, both groups showed a higher risk of BC, compared to the general female population. When the two groups were compared to each other, however, the risk of BC was significantly lower in autoantibody positive patients. Thus, as clearly stated in our article, among patients affected by thyroid diseases, the presence of thyroid autoantibodies may have a protective role against BC (Prinzi et al., 2014). As a consequence, the sentence reported by Shi and colleagues in the Discussion section of their article stating that their findings are in disagreement with our data is not correct and should be, if at all possible, amended

The size criteria in minimally invasive video-assisted thyroidectomy

BACKGROUND: Thyroid size is a very important criteria of MIVAT exclusion because the working space provided by the technique is limited. The aim of this work has been to verify the suitability of MIVAT and its applicability in clinical practice, not only in patients with a thyroid volume up to 25 ml but also in patients with a thyroid volume included from 25 to 50 ml. METHODS: From January 2003 to February 2006, 33 patients have been selected for MIVAT. A completely gasless procedure was carried out through a central 20 to 35 mm skin incision performed "high" between the cricoid and jugular notch. RESULTS: The patients were separated in 2 groups. The first group (less than 25 ml) included 23 patients, the second group (from 25 to 50 ml) included 10 patients. The skin incision performed was from 20 to 25 mm (mean 23.61 mm ± 1.83) long in the first group and from 25 to 35 mm (mean 27.8 mm ± 2.20) long in the second one; this difference is significant (t test p < 0.001). CONCLUSION: Our study suggest that the MIVAT using for thyroids bigger than 25 ml and up to 50 ml in volume is feasible and safe. This way allows more patients, excluded before, to take the advantages of minimally invasive approach

The minimally invasive open video-assisted approach in surgical thyroid diseases

BACKGROUND: The targets of minimally invasive surgery (MIVA) could be summarised by: achievement of the same results as those obtained with traditional surgery, less trauma, better post-operative course, early discharge from hospital and improved cosmetic results. The minimally invasive techniques in thyroid surgery can be described as either endoscopic "pure" approach (completely closed approach with or without CO(2 )insufflation), or "open approach" with central neck mini-incision or "open video-assisted approach". Traditionally, open thyroidectomy requires a 6 to 8 cm, or bigger, transverse wound on the lower neck. The minimally invasive approach wound is much shorter (1.5 cm for small nodules, up to 2–3 cm for the largest ones, in respect of the exclusion criteria) upon the suprasternal notch. Patients also experience much less pain after MIVA surgery than after conventional thyroidectomy. This is due to less dissection and destruction of tissues. Pathologies treated are mainly nodular goiter; the only kind of thyroid cancer which may be approached with endoscopic surgery is a small differentiated carcinoma without lymph node involvement. The patients were considered eligible for MIVA hemithyroidectomy and thyroidectomy on the basis of some criteria, such as gland volume and the kind of disease. In our experience we have chosen the minimally invasive open video-assisted approach of Miccoli et al. (2002). The aim of this work was to verify the suitability of the technique and the applicability in clinical practice. METHODS: A completely gasless procedure was carried out through a 15–30 mm central incision about 20 mm above the sternal notch. Dissection was mainly performed under endoscopic vision using conventional endoscopic instruments. The video aided group included 11 patients. All patients were women with a average age of 54. RESULTS: We performed thyroidectomy in 8 cases and hemithyroidectomy in 3 cases. The operative average time has been 170 minutes. CONCLUSION: Nowadays this minimally invasive surgery, in selected patients, clearly demonstrates excellent results regarding patient cure rate and comfort, with shorter hospital stay, reduced postoperative pain and most attractive cosmetic results

Increased expression of urokinase plasminogen activator and its cognate receptor in human seminomas

<p>Abstract</p> <p>Background</p> <p>The urokinase plasminogen activating system (uPAS) is implicated in neoplastic progression and high tissue levels of uPAS components correlate with a poor prognosis in different human cancers. Despite that, relative few studies are available on the expression and function of the uPAS components in human seminomas. In the present study we characterized the expression of the urokinase plasminogen activator (uPA), its cognate receptor (uPAR) and the uPA inhibitors PAI-1 and PAI-2 in normal human testis and seminomas.</p> <p>Methods</p> <p>The expression of the above genes was evaluated by means of quantitative RT-PCR, western blot, zymographic analysis and immunohistochemistry.</p> <p>Results</p> <p>Quantitative RT-PCR analysis of 14 seminomas demonstrated that uPA and uPAR mRNAs were, with respect to control tissues, increased in tumor tissues by 3.80 ± 0.74 (p < 0.01) and 6.25 ± 1.18 (p < 0.01) fold, respectively. On the other hand, PAI-1 mRNA level was unchanged (1.02 ± 0.24 fold), while that of PAI-2 was significantly reduced to 0.34 ± 0.18 (p < 0.01) fold. Western blot experiments performed with protein extracts of three seminomas and normal tissues from the same patients showed that uPA protein levels were low or undetectable in normal tissues and induced in tumor tissues. On the same samples, zymographic analysis demonstrated increased uPA activity in tumor tissue extracts. Western blot experiments showed that also the uPAR protein was increased in tumor tissues by 1.83 ± 0.15 fold (p < 0.01). The increased expression of uPA and uPAR was further confirmed by immunohistochemical staining performed in 10 seminomas and autologous uninvolved peritumoral tissues. Finally, variation in the mRNA level of PAI-1 significantly correlated with tumor size.</p> <p>Conclusions</p> <p>We demonstrated the increased expression of uPA and uPAR in human seminomas with respect to normal testis tissues, which may be relevant in testicular cancer progression.</p

Aurora kinases are expressed in medullary thyroid carcinoma (MTC) and their inhibition suppresses in vitro growth and tumorigenicity of the MTC derived cell line TT

International audienceBACKGROUND: The Aurora kinase family members, Aurora-A, -B and -C, are involved in the regulation of mitosis, and alterations in their expression are associated with cell malignant transformation. To date no information on the expression of these proteins in medullary thyroid carcinoma (MTC) are available. We here investigated the expression of the Aurora kinases in human MTC tissues and their potential use as therapeutic targets. METHODS: The expression of the Aurora kinases in 26 MTC tissues at different TNM stages was analyzed at the mRNA level by quantitative RT-PCR. We then evaluated the effects of the Aurora kinase inhibitor MK-0457 on the MTC derived TT cell line proliferation, apoptosis, soft agar colony formation, cell cycle and ploidy. RESULTS: The results showed the absence of correlation between tumor tissue levels of any Aurora kinase and tumor stage indicating the lack of prognostic value for these proteins. Treatment with MK-0457 inhibited TT cell proliferation in a time- and dose-dependent manner with IC50 = 49.8 ± 6.6 nM, as well as Aurora kinases phosphorylation of substrates relevant to the mitotic progression. Time-lapse experiments demonstrated that MK-0457-treated cells entered mitosis but were unable to complete it. Cytofluorimetric analysis confirmed that MK-0457 induced accumulation of cells with ≥ 4N DNA content without inducing apoptosis. Finally, MK-0457 prevented the capability of the TT cells to form colonies in soft agar. CONCLUSIONS: We demonstrate that Aurora kinases inhibition hampered growth and tumorigenicity of TT cells, suggesting its potential therapeutic value for MTC treatment