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Andreas Machens Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany

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Henning Dralle Department of General, Visceral and Transplantation Surgery, Section of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany

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Genetic association studies hinge on definite clinical case definitions of the disease of interest. This is why more penetrant mutations were overrepresented in early multiple endocrine neoplasia type 2 (MEN2) studies, whereas less penetrant mutations went underrepresented. Enrichment of genetic association studies with advanced disease may produce a flawed understanding of disease evolution, precipitating far-reaching surgical strategies like bilateral total adrenalectomy and 4-gland parathyroidectomy in MEN2. The insight into the natural course of the disease gleaned over the past 25 years caused a paradigm shift in MEN2: from the removal of target organs at the expense of greater operative morbidity to close biochemical surveillance and targeted resection of adrenal tumors and hyperplastic parathyroid glands. The lead time provided by early identification of asymptomatic MEN2 carriers under biochemical surveillance delimits a ‘window of opportunity’, within which (i) pre-emptive total thyroidectomy alone is adequate, circumventing morbidity attendant to central node dissection; (ii) subtotal ‘tissue-sparing’ adrenalectomy is sufficient, trading the risk of steroid dependency for the risk of a second pheochromocytoma in the adrenal remnant and (iii) parathyroidectomy is limited to enlarged glands, trading the risk of postoperative hypoparathyroidism for the risk of leaving behind hyperactive parathyroid glands. Future research should delineate further the mutation-specific, age-dependent penetrance of pheochromocytoma and primary hyperparathyroidism to refine the risk-oriented approach to MEN2. The sweeping changes in the management of MEN2 since the new millenium hold the hope that death and major morbidity from this uncommon disease can be eliminated in our lifetime.

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Andreas Machens General, Pathology, Departments of

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Steffen Hauptmann General, Pathology, Departments of

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Henning Dralle General, Pathology, Departments of

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Rearranged during transfection (RET) germ-line mutations in exon 10 are peculiar because they produce both gain-of-function multiple endocrine neoplasia 2A and loss-of-function Hirschsprung's disease phenotypes. Drawing on 38 medullary thyroid cancer patients harboring germ-line mutations in codon 620 (n=8), 618 (n=19), 611 (n=10), and 609 (n=1), this study aimed to test the hypothesis that closer proximity of RET germ-line mutations in exon 10 to the cell membrane may translate into earlier or more advanced disease. The closer mutations in codon 620, 618, and 611 were located to the transmembrane domain (codons 657–636) of the RET receptor, the greater were mean primary tumor diameters (23.5, 18.7, and 7.5 mm, P=0.020), the frequency of lymph node metastasis (75, 68, and 30%, P=0.11) and pheochromocytoma (38, 16, and 0%, P=0.11). Periods of observation were broadly comparable for these groups (mean age 33.4–39.3 years; P=0.71). When mutations in adjoining codons were collapsed (codons 620/618 vs 611/609), the differences in mean primary tumor diameter (20.1 vs 7.4 mm, P=0.005) and lymph node metastasis (70 vs 36%; P=0.07) were accentuated. Compared with 80 carriers of exon 11 mutations (codon 634, n=78; codon 630, n=2), the 38 carriers of exon 10 mutations, which are rarer and confer a weaker transforming activity in vitro than exon 11 mutations, required significantly more time to develop fewer tumors. Although limited in numbers, these data suggested that membrane proximity is an important determinant of tumor development in carriers of RET mutations in exon 10.

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Andreas Machens Medical Faculty, Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany

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Kerstin Lorenz Medical Faculty, Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany

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Frank Weber Department of General, Visceral and Transplantation Surgery, Section of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany

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Henning Dralle Department of General, Visceral and Transplantation Surgery, Section of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany

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Andreas Machens Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06097 Halle (Saale), Germany

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Florian Hoffmann Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06097 Halle (Saale), Germany

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Carsten Sekulla Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06097 Halle (Saale), Germany

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Henning Dralle Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06097 Halle (Saale), Germany

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Men and women differ in thyroidal C-cell mass and calcitonin secretion. This difference may have implications for the definition of calcitonin thresholds to distinguish sporadic C-cell hyperplasia from occult medullary thyroid cancer. This retrospective study examined the hypothesis that gender-specific calcitonin thresholds predict occult medullary thyroid cancer more accurately among patients with increased basal calcitonin levels than unisex thresholds. A total of 100 consecutive patients were evaluated with occult sporadic C-cell disease no larger than 10 mm who were referred for increased basal calcitonin levels and underwent pentagastrin stimulation preoperatively at this institution. Altogether, gender-specific calcitonin thresholds predicted medullary thyroid cancer better than unisex thresholds. At lower (≤50 pg/ml basally; ≤500 pg/ml after stimulation), but not higher, calcitonin serum levels, women revealed medullary thyroid cancer four to eight times more often than men. Most discriminatory between C-cell hyperplasia and medullary thyroid cancer was a basal calcitonin threshold of 15 pg/ml (corrected 20 pg/ml) for women and 80 pg/ml (corrected 100 pg/ml) for men, based on the greatest accuracy at the lowest possible calcitonin level. The respective gender-specific stimulated peak calcitonin thresholds were 80 pg/ml (corrected 100 pg/ml) and 500 pg/ml. Corresponding positive predictive values for medullary thyroid cancer at these calcitonin thresholds were 89 and 90% for women, as opposed to 100% for men. To increase the positive predictive value for women to 100%, the respective calcitonin thresholds would have to be raised to 40 pg/ml (corrected 50 pg/ml) and 250 pg/ml. These findings indicate that gender-specific calcitonin thresholds predict sporadic occult medullary thyroid cancer better than unisex thresholds.

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Andreas Machens Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany

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Kerstin Lorenz Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany

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Frank Weber Department of General, Visceral and Transplantation Surgery, Division of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany

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Henning Dralle Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany
Department of General, Visceral and Transplantation Surgery, Division of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany

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Thyroid cancer is the only nonreproductive cancer with striking female predominance, although men with thyroid cancer develop more aggressive disease. This study aimed to quantify sex-specific differences in medullary thyroid cancer (MTC) spread after controlling for primary thyroid tumor size. Included in this retrospective analysis were all patients with unilateral solitary MTC who underwent initial neck surgery at a tertiary referral center. A total of 565 patients, 255 men and 310 women, were identified, of whom 467 had sporadic and 98 hereditary MTC. When stratified by sex, and after correction for multiple testing, men had higher preoperative basal calcitonin levels (medians of 655 vs 181 pg/mL; P < 0.001), more frequent extrathyroid extension (25 vs 9%; P < 0.001) and node metastasis (53 vs 27%; P < 0.001) with more involved nodes (medians of 2 vs 0 nodes; P < 0.001) than women but achieved less often biochemical cure (53 vs 74%; P < 0.001). Although absent in patients with very small (≤5 mm) thyroid tumors, sex disparities were immediately apparent in patients with 5.1–40 mm (node metastasis and biochemical cure) and 10.1–40 mm (extrathyroid extension) large thyroid tumors but were lost in patients with thyroid tumors >40 mm as women caught up. Sex disparities were strongest for node metastasis with a 27–41% (overall 24.0%) point difference, followed by biochemical cure with a −15–35% (overall −20.3%) point difference and extrathyroid extension with a 17–24% (14.2% overall) point difference. These findings indicate that the male predominance in MTC aggressiveness is largely biologically driven, warranting further research.

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Vera Tiedje Department of Endocrinology, Diabetology and Metabolism, Endocrine Tumour Center at West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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Martin Stuschke Department of Radiotherapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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Frank Weber Department of General, Visceral and Transplantation Surgery, Section of Endocrine Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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Henning Dralle Department of General, Visceral and Transplantation Surgery, Section of Endocrine Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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Laura Moss Velindre Cancer Centre, Cardiff, Wales, UK

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Dagmar Führer Department of Endocrinology, Diabetology and Metabolism, Endocrine Tumour Center at West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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Anaplastic thyroid carcinoma (ATC) is an orphan disease and in most patients fatal. So far no established treatment is available that prolongs survival. Several large retrospective studies have identified negative prognostic markers, analyzed efficacy of multimodal approaches such as radiotherapy with and without concurrent chemotherapy and chemotherapy protocols. Recently, single case reports have suggested some effectiveness of newer therapies targeting single somatic alterations in ATC. Overall, the conclusions that can be drawn from published retrospective studies and the scarce prospective approaches is that new treatment protocols should be developed including surgery, radiotherapy, chemotherapy and targeted therapy approaches and combinational therapy with immunotherapies. These protocols then need to be evaluated prospectively to improve ATC patients’ outcome in routine care.

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Bogusz Trojanowicz AG Experimentelle and Chirurgische Onkologie, Allgemein-, Kinderchirurgie, Universitätsklinik und Poliklinik für
AG Experimentelle and Chirurgische Onkologie, Allgemein-, Kinderchirurgie, Universitätsklinik und Poliklinik für

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Lars Brodauf AG Experimentelle and Chirurgische Onkologie, Allgemein-, Kinderchirurgie, Universitätsklinik und Poliklinik für

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Carsten Sekulla AG Experimentelle and Chirurgische Onkologie, Allgemein-, Kinderchirurgie, Universitätsklinik und Poliklinik für

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Kerstin Lorenz AG Experimentelle and Chirurgische Onkologie, Allgemein-, Kinderchirurgie, Universitätsklinik und Poliklinik für

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Rainer Finke AG Experimentelle and Chirurgische Onkologie, Allgemein-, Kinderchirurgie, Universitätsklinik und Poliklinik für

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Henning Dralle AG Experimentelle and Chirurgische Onkologie, Allgemein-, Kinderchirurgie, Universitätsklinik und Poliklinik für

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Cuong Hoang-Vu AG Experimentelle and Chirurgische Onkologie, Allgemein-, Kinderchirurgie, Universitätsklinik und Poliklinik für

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AUF1/heterogeneous nuclear ribonucleoprotein D is an adenylate–uridylate-rich elements (AREs) -binding protein, which regulates the mRNA stability of many genes related to growth regulation, such as proto-oncogenes, growth factors, cytokines, and cell cycle-regulatory genes. Several studies demonstrated AUF1 involvement in the processes of apoptosis, tumorigenesis, and development by its interactions with ARE-bearing mRNAs. We report here that AUF1 may be involved in thyroid carcinoma progression. Investigations on thyroid tissues revealed that cytoplasmic expression of AUF1 in malignant tissues was increased when compared with benign thyroid tissues. In thyroid carcinoma cell lines, AUF1 was mostly detectable in the nucleus; however, in dividing cells, its increased production was also observed in the cytoplasm. We found AUF1 in complexes with ARE-bearing mRNAs, previously described to be crucial for proliferation and cell cycle of thyroid carcinoma. Total or exon-selective knockdown of AUF1 led to growth inhibition accompanied by induction of cell cycle inhibitors and decreased levels of cell cycle promoters. Our data demonstrate the existence of a complex network between AUF1 and mRNAs encoding proteins related to cell proliferation. AUF1 may control the balance between stabilizing and destabilizing effects, both of which are exerted on cell cycle machinery in thyroid carcinoma. Although we cannot exclude participation of other factors, thyroid carcinoma may recruit cytoplasmic AUF1 to disturb the stability of mRNAs encoding cyclin-dependent kinase inhibitors, leading to uncontrolled growth and progression of tumor cells. Thus, AUF1 may be considered as a new, additional marker for thyroid carcinoma.

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Andreas Machens Medical Faculty, Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany

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Kerstin Lorenz Medical Faculty, Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany

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Frank Weber Department of General, Visceral and Transplantation Surgery, Division of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany

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Tim Brandenburg Department of Endocrinology, Diabetology and Metabolism, University of Duisburg-Essen, Essen, Germany

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Dagmar Führer-Sakel Department of Endocrinology, Diabetology and Metabolism, University of Duisburg-Essen, Essen, Germany

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Henning Dralle Medical Faculty, Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
Department of General, Visceral and Transplantation Surgery, Division of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany

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The age-specific development of the three constituent components of multiple endocrine neoplasia type 2 (MEN 2) is incompletely characterized for many of the >30 causative rearranged during transfection (RET) mutations, which this genetic association study aimed to specify. Included in the study were 683 carriers of heterogeneous RET germline mutations: 53 carriers with 1 highest-risk mutation (codon 918); 240 carriers with 8 different high-risk mutations (codon 634); 176 carriers with 16 different intermediate-risk mutations (codon 609, 611, 618, 620, or 630); and 214 carriers with 6 different low-risk mutations (codon 768, 790, 804, or 891).There was a strong genotype-specific development of MEN 2 constituent components, with distinct age gradients from C cell disease to node negative medullary thyroid cancer (MTC), from node negative to node positive MTC, from node positive MTC to pheochromocytoma, and from pheochromocytoma to primary hyperparathyroidism. Primary hyperparathyroidism was not observed among the 53 MEN 2B patients who carried highest-risk mutations (age range: 0.5–50 years), of whom no more than 12 (23%) and 3 (6%) carriers were older than age 30 years and 35 years, respectively. The age-specific development of MTC differed significantly between the four RET risk categories, whereas the age-specific development of pheochromocytoma differed significantly only between the two strongest RET risk categories. No significant differences were noted in the development of primary hyperparathyroidism. These findings delineate age-specific disease manifestation corridors for the three constituent components of MEN 2 by RET genotype. These corridors are useful for initial risk assessment and organ-specific surveillance of newly identified RET carriers going forward.

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Denise Zwanziger Department of Endocrinology and Metabolism, Institute of Pathology, Department of Pathology, Department of General-, University Hospital Essen

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Julia Badziong Department of Endocrinology and Metabolism, Institute of Pathology, Department of Pathology, Department of General-, University Hospital Essen

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Saskia Ting Department of Endocrinology and Metabolism, Institute of Pathology, Department of Pathology, Department of General-, University Hospital Essen

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Lars Christian Moeller Department of Endocrinology and Metabolism, Institute of Pathology, Department of Pathology, Department of General-, University Hospital Essen

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Kurt Werner Schmid Department of Endocrinology and Metabolism, Institute of Pathology, Department of Pathology, Department of General-, University Hospital Essen

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Udo Siebolts Department of Endocrinology and Metabolism, Institute of Pathology, Department of Pathology, Department of General-, University Hospital Essen

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Claudia Wickenhauser Department of Endocrinology and Metabolism, Institute of Pathology, Department of Pathology, Department of General-, University Hospital Essen

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Henning Dralle Department of Endocrinology and Metabolism, Institute of Pathology, Department of Pathology, Department of General-, University Hospital Essen

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Dagmar Fuehrer Department of Endocrinology and Metabolism, Institute of Pathology, Department of Pathology, Department of General-, University Hospital Essen

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CLAUDIN-1 belongs to the family of transmembrane tight junction proteins tightening the paracellular cleft of epithelial cells. In human malignancies, CLAUDIN-1 is often dysregulated and located in subcellular compartments, particularly in the nucleus where it may influence cellular behaviour. Here, we studied CLAUDIN-1 in relation to the biological characteristics of follicular thyroid carcinoma (FTC). CLAUDIN-1 immuno-staining showed loss of membrane expression and increased nuclear CLAUDIN-1 localization in FTC metastases. CLAUDIN-1 function was further investigated in two different follicular thyroid carcinoma cell lines: FTC-133 isolated from a regional lymph node metastasis and FTC-238 derived from a lung metastasis. In both cell lines CLAUDIN-1 expression was demonstrated in the cell nuclei with a significantly higher protein expression in FTC-238 compared to FTC-133 cells. Interestingly, in vitro scratch assay revealed enriched nuclear CLAUDIN-1 expression near the scratch. Furthermore, the increase of the pathogenic character of FTC-133 cells by RASV12 transfection was associated with elevated CLAUDIN-1 expression and enhanced cell migration, invasion and proliferation. Likewise over-expression of nuclear CLAUDIN-1 in FTC-133 cells resulted in increased cell migration and invasion. Conversely, CLAUDIN-1 downregulation in FTC-238 cells by siRNA resulted in decreased cell migration and invasion and was accompanied by reduced phosphoPKC expression. Moreover, activation and inhibition of PKC resulted in CLAUDIN-1 up- and downregulation in FTC cells respectively. These data suggest an impact of CLAUDIN-1 on follicular thyroid carcinoma aggressiveness, which could potentially be influenced by PKC activity.

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Stefan Karger
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Carl Weidinger
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Kerstin Krause
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Sien-Yi Sheu Division of Endocrinology and Diabetes, Institute of Pathology and Neuropathology, Institute of Pathology, Department of Surgery, Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Street 27, 04103 Leipzig, Germany

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Thomas Aigner Division of Endocrinology and Diabetes, Institute of Pathology and Neuropathology, Institute of Pathology, Department of Surgery, Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Street 27, 04103 Leipzig, Germany

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Oliver Gimm Division of Endocrinology and Diabetes, Institute of Pathology and Neuropathology, Institute of Pathology, Department of Surgery, Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Street 27, 04103 Leipzig, Germany

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Kurt-Werner Schmid Division of Endocrinology and Diabetes, Institute of Pathology and Neuropathology, Institute of Pathology, Department of Surgery, Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Street 27, 04103 Leipzig, Germany

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Henning Dralle Division of Endocrinology and Diabetes, Institute of Pathology and Neuropathology, Institute of Pathology, Department of Surgery, Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Street 27, 04103 Leipzig, Germany

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Dagmar Fuhrer
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The forkhead box transcription factor FOXO3a has recently been identified as central mediator of the cellular response to oxidative stress inducing cell cycle arrest or apoptosis. The aim of our study was to investigate the regulation of FOXO3a in the thyroid and to determine whether alterations in FOXO3a activity occur in thyroid carcinogenesis. In vitro, we demonstrate that FOXO3a activity is negatively regulated by the PI3K/Akt cascade promoting increased phosphorylation and cytoplasmatic accumulation of FOXO3a with decreased transcription of the target genes p27kip (CDKN1B) and Bim (BCL2L11), but increased expression of GADD45A. By contrast, we show that H2O2 exposure activates FOXO3a in thyrocytes with JNK (MAPK8)-mediated nuclear accumulation of FOXO3a and increased expression of the cell cycle arrest genes p27kip and GADD45A. In vivo, we observed a marked cytoplasmatic accumulation of FOXO3a in differentiated thyroid cancers versus an exclusive nuclear accumulation in follicular adenoma and normal thyroid tissue. Moreover, this cytosolic accumulation of FOXO3a correlated with an increased phospho-Akt expression in thyroid malignancies and was accompanied by decreased expression of the FOXO targets p27kip and Bim and an increase in GADD45A mRNA expression in the thyroid cancers. Our data suggest FOXO3a as a novel player of cellular stress response in the thyroid, mediating the thyrocyte's fate either to survive or to undergo apoptosis. Furthermore, PI3K-dependent FOXO3a inactivation may be a novel pathomechanism for the escape from apoptosis in thyroid cancer cells, in particular in follicular thyroid carcinoma.

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