Thyroid Transcription Factor-1 Protein Expression Research Articles

Thyroid transcription factor-1 expression prevalence and its clinical implications in non-small cell lung cancer: a high-throughput tissue microarray and immunohistochemistry study

Thyroid transcription factor 1 (TTF-1), a homeodomain-containing transcription factor, plays a pivotal role in lung development, cell growth, and differentiation processes. The current literature reports considerable variation in frequency of TTF-1 protein expression in human non-small cell lung cancer (NSCLC). TTF-1 expression has not been extensively investigated as a prognostic marker in NSCLC. To assess the prevalence of TTF-1 expression, and to evaluate its potential role in disease prognosis, 140 stage I–IIIA NSCLCs with long-term follow-up were studied under uniform conditions using high-density tissue microarray (TMA) combined with immunohistochemistry. Patient survival and association of TTF-1 expression with clinicopathologic parameters were analyzed. One hundred twenty-six tumor samples were fully assessable after tissue processing. Sixty-four samples (50.8%) expressed TTF-1 and 62 (49.2%) displayed no expression. TTF-1 expression was significantly ( P < 0.001) correlated with histological subtype: 51 adenocarcinomas (AdCs) (51 of 75; 68%) versus 9 squamous cell carcinomas (SCCs) (9 of 43; 21%) were TTF-1 positive. TTF-1 expression, performance status, nodal status, and tumor stage were significantly related to patient survival. In multivariate analysis, positive TTF-1 expression tended to favor a better patient outcome ( P = 0.05). Overall, NSCLC patients with positive TTF-1 expression had a median survival of greater than 57.3 months, whereas those with negative expression had a median survival of 39.4 ± 5.2 months (log-rank test, P = 0.0067). In this study we found that TTF-1 is predominately expressed in adenocarcinoma. The loss of TTF-1 expression was associated with aggressive behavior of NSCLCs. The results from this study strongly indicate that further investigation is warranted to better define the role of TTF-1 as a prognostic factor in this malignancy.

Thyroid Transcription Factor � 1 (TTF-1) Immunoexpression in Thyroid Carcinoma with Follicular Origin

Differentiated thyroid carcinomas are heterogeneous diseases with clinical and morphological features insufficient to predict their clinical behavior. The expression of tissue-specific transcription factors that control differentiated phenotype can be an additional method in evaluating the aggressiveness of a tumor, when differentiation markers and malignant phenotype of tumor cells are inconclusive. The expression of thyroid transcription factor-1 (TTF-1) is limited to thyroid follicular cells; it is a nuclear protein expressed in the epithelial cells of the thyroid, lungs and diencephalon. Using the monoclonal mouse antibody, clone 8G7G3/1, we examined the immunohistochemical expression of TTF-1 protein in 26 thyroid carcinomas (22 papillary carcinomas � PTC, 2 follicular carcinomas � FTC, 2 anaplastic carcinomas - AC), 4 follicular adenomas � FA, 10 benign thyroid lesions as underlying diseases (multinodular goiter � 3, Hashimoto thyroiditis � 3, Graves Basedow disease - 4) and sections of normal thyroid tissue, assessing the possible correlations with clinical and morphological features, as well as patient outcomes.TTF-1 nuclear expression was identified in 75% of benign thyroid lesions and 18/26 (69.23%) carcinomas. We noted TTF-1 nuclear expression in 68.18% of PTC (10% being associated with recurrent disease) and the absence of immunoreaction in 31.82% of PTC without recurrent disease. In patients with PTC, the risk of recurrence was significantly associated with the presence of nuclear TTF-1 expression in the primary tumor (p[0.001), but was not influenced by the type of surgery performed (p]0.05) or patients� age. TTF-1 nuclear expression did not correlate with patients� gender, tumor size, extent of disease at the moment of diagnosis and multifocal tumors (p]0.05). TTF-1 nuclear reactivity can be elevated in differentiated thyroid tumors (PTC and FTC) with aggressive clinical behavior that will develop recurrent or persistent disease. In anaplastic thyroid carcinomas with fast growth rate, immunoreactivity for TTF-1 and Ki-67 can offer useful information for tumor cell differentiation, while in the case of a mixed thyroid tumor it helps in distinguishing between well differentiated and undifferentiated/anaplastic areas.

Effect of Primary Hypothyroidism on Fetal Mouse Lung Surfactant Protein A, B and C, and Thyroid Transcription Factor-1 Protein and Gene Expression.† 1456

Primary hypothyroidism in the Hyt/Hyt mice is due to a point mutation(Pro-556-Leu) in the β subunit of the TSH receptor of the thyroid gland and is transmitted as an autosomal recessive trait. Fetal hypothyroidism is associated with delayed fetal lung ultrastructural maturation (Ped. Res. 36:380:94). Surfactant proteins (SP-A, B & C) & Thyroid Transcription Factor-1 (TTF-1) play an important role in fetal lung surfactant function and type II cell differentiation, but the effect of primary hypothyroidism on the developmental expression of fetal lung SP-A, SP-B, SP-C or TTF-1 has not been investigated. Hyt/Hyt mice identified by high serum TSH and low free T4 levels were made euthyroid by supplemental T3. The mice were then bred to carry Hyt/Hyt pups. Balb-c euthyroid mice served as controls. All mice were killed on d 18 of gestation (term ≈20 d, vaginal plug = d 1 of pregnancy). Fetal lung immunostaining for SP-A, SP-B, SP-C and TTF-1 was performed and gene expression of these proteins was determined by Northern blot analysis. The TTF-1 immunoreactivity was nuclear in localization and confined to the type II cells, while staining for SP-A, SP-B and SP-C was cytoplasmic and present in type II cells as well as within the alveolar lumen. The intensity and distribution of the immunoreactivity scored on a scale of 0 to 3, for SP-A, SP-B and SP-C and TTF-1 (n=5) was markedly decreased in the Hyt/Hyt fetal lungs when compared to the controls (n=5). While gene expression for SP-C(≈0.8 kb) and TTF-1 (≈2.3 kb) was significantly decreased in the hyt/hyt mice, the gene expression for SP-B (≈0.9 kb) was similar in both groups. CON: Primary hypothyroidism is associated with a delay in the developmental expression of fetal lung SP-A, SP-B, SP-C and TTF-1 protein, and a differential expression for SP-B, SP-C and TTF-1 genes. These findings may explain a higher incidence of RDS in human neonates with hypothyroidism(NIH-HL 52839).

Interferon-gamma suppresses thyrotropin receptor promoter activity by reducing thyroid transcription factor-1 (TTF-1) binding to its recognition site.

Interferon-gamma (IFN gamma) is known to suppress the expression of thyroid-specific genes, such as thyroglobulin, thyroid peroxidase, and the TSH receptor (TSHR). In the present study, we show that this reflects, in part, a transcriptional action mediated by thyroid transcription factor-1 (TTF-1). Thus, transfected into rat FRTL-5 cells, the activity of reporter plasmids, containing rat TSHR promoter ligated to a chloramphenicol acetyltransferase gene, was significantly suppressed in the presence of rat IFN gamma. A -199-bp promoter construct showed the greatest suppression by IFN gamma whereas a -177-bp construct, in which the TTF-1 binding site was deleted, showed less suppressibility. The suppressive effect was rat IFN gamma-specific, since human IFN alpha, -beta, and -gamma exhibited no significant effects. The effect was concentration-dependent from 3-50 U/ml. In FRT rat thyroid cells that do not express TTF-1, IFN gamma-induced suppression on the promoter activity was not observed. In addition, when the TTF-1 binding site was mutated so that TTF-1 can not bind, IFN gamma-induced suppression was significantly reduced. In gel mobility shift analyses, a protein-DNA complex formed by TTF-1 was reduced when the nuclear extract prepared from IFN gamma-treated FRTL-5 cells was used; however, expression of TTF-1 mRNA and TTF-1 protein, which were assessed by Northern blot analysis and Western blot analysis, respectively, were not affected by IFN gamma treatment of FRTL-5 cells. Instead, reduction of DNA-binding affinity of TTF-1 was evident when competition analysis was performed in gel mobility shift analysis. From these results, we conclude that IFN gamma suppresses TSHR promoter activity, in part, by reducing TTF-1 binding to its recognition site. We also raise the possibility that the suppressive effect of IFN gamma on promoter activity is mediated by additional element(s) and factor(s) downstream of the TTF-1 site.