Role Of Thyroid Transcription Factor-1 Research Articles

The role of thyroid transcription factor-1 in differentiating lung adenocarcinomas from non-pulmonary adenocarcinoma effusions.

Effusions, characterized by abnormal fluid accumulations in body cavities, present difficulties in identifying the primary organs of metastatic tumors through cytopathologic investigation, particularly in cancer-related complications. This retrospective cross-sectional laboratory study aimed to investigate the role of thyroid transcription factor-1 (TTF-1) in distinguishing lung adenocarcinomas from non-pulmonary adenocarcinomas in effusions. The study was conducted at Almobarak Cytopathology Laboratory, a private cytopathology laboratory. H&E was used to confirm the histological diagnosis of 58 archived cell blocks. TTF-1 immunostaining patterns were then correlated with the histological diagnosis. Statistical analysis, including numerical and graphical data summaries, was conducted using the Chi-square test in SPSS 23. TTF-1 expression was observed in 20 (34.4%) cases, while 38 (65.5%) cases showed no TTF-1 reaction. Positive TTF-1 was found in pleural fluid in 61.1 % of lung adenocarcinomas, while negative TTF-1 was found in only 3.4%. TTF-1 was not detected in the majority of peritoneal fluid samples. There was a highly significant relationship between pleural fluid, TTF-1, and lung adenocarcinoma (p=0.000). The data provided further evidence that TTF-1 is a useful marker for distinguishing pulmonary adenocarcinomas from non-pulmonary adenocarcinoma tumors.

The prognostic role of thyroid transcription factor-1 in lung adenocarcinoma.

In this study, we investigated the expression of thyroid transcription factor-1 (TTF-1) in lung adenocarcinoma patients' samples and analyzed the association of TTF-1 with clinicopathological parameters, prognosis, and treatment options in patients with lung adenocarcinoma. This retrospective study enrolled 200 patients who were histologically confirmed lung adenocarcinoma with Stage I-IV disease, between 2008 and 2015 years. The cytological archive of these hospitals' Pathology Department was searched. The available slides and the clinical information were reviewed and correlated. All analyses were conducted by SPSS version 15.0 statistical software. Sixty-five (32.5%) of the patients showed TTF-1 negativity and 135 (67.5%) of them showed TTF-1 positivity. The median survival for TTF-1 positive and negative patients was 19.6 and 12.2 months, respectively. We did not find any statistical significance in-between the parameters in terms of the survival data. In TTF-1-negative group, the survival time of epidermal growth factor receptor mutation positive (P = 0.049), cytokeratin 7 (CK7) positive (P = 0.009) patients and those who had received curative radiotherapy (P = 0.028) was significantly better as compared to TTF-1-positive group. We also analyzed the relation between TTF-1 and survival outcome or chemotherapy selection in Stage IV disease. We could not identify any correlation between TTF-1 and survival outcome or treatment selection. This study suggests that TTF-1 is not a favorable prognostic factor in lung adenocarcinoma patients. The prognostic role of CK7 and relationship between TFF-1 expression in lung adenocarcinoma and predictive role of TTF-1 expression for the selection of first-line treatment in Stage IV lung adenocarcinoma should be validated in prospective and randomized studies.

Prognostic Value of Thyroid Transcription Factor-1 Expression in Patients with Advanced Lung Adenocarcinoma.

The prognostic role of thyroid transcription factor-1 (TTF1) in advanced lung cancer is not clearly established. The present study aimed to evaluate the associations between clinicopathological characteristics, TTF1 expression, and overall survival (OS) of patients with advanced lung adenocarcinoma. One hundred and seventy-two patients were enrolled in this retrospective study. OS was assessed according to immunohistochemical TTF1 expression in lung adenocarcinoma tissue, age, gender, performance status (PS), smoking history and status, disease stage, tumor differentiation, epidermal growth factor receptor (EGFR) mutation and EGFR tyrosine kinase inhibitor (TKI) treatment status. The OS time was longer (p<0.001) for patients with TTF1 expression than for patients without TTF1 expression (13.0 vs. 5.0 months, respectively). A multivariate analysis confirmed that worse PS [hazard ratio (HR)=2.13, p<0.001], poor histological differentiation (HR=2.02, p=0.001), wild-type EGFR status (HR=3.08, p<0.001) and negative TTF1 expression (HR=1.97, p=0.001) were independent predictors of worse prognosis. TTF1 expression is an independent predictor of survival of patients with advanced lung adenocarcinoma.

Role of thyroid transcription factor-1 in transcriptional regulation of heme oxygenase-1

Here, we report thyroid transcription factor 1 (TTF-1) as an important transcription factor for the expression of heme oxygenase-1 (HO-1). HO-1 is a well-known cytoprotective enzyme against inflammation. We observed that HO-1 co-expressed with TTF-1 in mouse hypothalamic cells. Results from luciferase and chromatin immunoprecipitation assays revealed that TTF-1 directly activated HO-1 transcription by binding to binding domains in the 5′-flanking region of the HO-1 gene. A proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α), induced nuclear translocation of TTF-1 and increased binding affinity of TTF-1 to its binding sites on the HO-1 gene. HO-1 mRNA increased with TTF-1 overexpression but decreased with RNA interference of TTF-1 expression in rat astroglial C6 cells. Together with results showing involvement of TTF-1 in the TNF-α-induced increase in interleukin 1 beta and monocyte chemotactic protein 1 production, this study suggests that TTF-1 plays an important role in the mouse hypothalamus TNF-α-induced inflammatory response for regulating HO-1 gene expression.

The role of Thyroid Transcription Factor-1 and Tumor differentiation in Resected Lung Adenocarcinoma

To investigate the role of thyroid transcription factor-1 (TTF-1) and tumor differentiation in resected lung adenocarcinoma. A total of 520 patients with clinical early stage lung adenocarcinoma who underwent surgical resection were reviewed retrospectively. Clinical data and outcomes were evaluated with an average follow-up of 117 months. The results were validated via lung cancer cell line studies. The clinical parameters did not differ between relapse and nonrelapse patients. Exceptions were tumor differentiation, lymphovascular space invasion, F18-fluorodeoxyglucose maximum standard uptake value, tumor size, and pathological stage (p < 0.001). Poor tumor differentiation was the independent prognostic factor (odds ratio: 2.937, p = 0.026). The expression of TTF-1 was correlated with tumor differentiation in resected lung adenocarcinoma patients (p < 0.001). Five-year survival was 60.0% for score 1 TTF-1 expression patients, 80.1% for score 2 TTF-1 expression patients, and 86.1% for score 3 TTF-1 expression group patients. The lung cancer cell line study of knockdown and overexpression of TTF-1 revealed TTF-1 mediated High Mobility Group AT-Hook 2 (HMGA2) protein involved with epithelium-mesenchymal transformation. The chromatin immunoprecipitation revealed TTF-1 regulated HMGA2 via direct binding. TTF-1/HMGA2 axis was associated with tumor differentiation and mediated the aggressiveness of the tumor and prognosis.

Thyroid transcription factor-1 expression in advanced non- small cell lung cancer: impact on survival outcome.

The prognostic role of thyroid transcription factor-1 (TTF-1) expression in lung cancer has been assessed but with inconsistent results. The present study aimed to evaluate the prognostic value of TTF1 expression in advanced non-squamous non-small cell lung cancer (NSCLC). In this retrospective study, patients with stage IIIB-IV non-squamous NSCLC were enrolled. Progression free survival (PFS) and overall survival (OS) were assessed according to TTF1 expression status, age categories (≤60 vs >60 years), gender, performance status (PS) (0-2 vs 3-4), type of 1st line chemotherapy (pemetrexed containing vs others) and EGFR status. A total of 120 patients were included. In univariate analysis, PFS was improved in patients with PS 0-2 (7.0 vs 2.0 months, p=0.002) and those who received pemetrexed-containing chemotherapy (9.2 vs 5.8 months, p=0.004). OS was improved in female patients (23.0 vs 8.7 months, p<0.0001), PS 0-2 (14.4 vs 2.0 months, p<0.0001), those with pemetrexed-containing chemotherapy (17.0 vs 11.0 months, p=0.019), TTF1-positive (12.8 vs 5.8 months, p=0.011) and EGFR- mutant patients (23.0 vs 11.7 months, p=0.006). In multivariate analysis, male gender (HR=2.34, p=0.025) and non-pemetrexed containing therapy (HR=2.24, p=0.022) were independent predictors of worse PFS. Wild EGFR status (HR=2.49, p=0.015) and male gender (HR=2.78, p=0.008) were predictors of worse OS. Pemetrexed-containing therapy significantly improved PFS while OS was improved in EGFR mutant patients. Female patients had better PFS and OS. TTF1 expression was not a prognostic marker in advanced non-squamous NSCLC.

Role of thyroid transcription factor-1 and P63 immunocytochemistry in cytologic typing of non-small cell lung carcinomas

PurposeEvaluation of the value of thyroid transcription factor (TTF-1) and P63 in subtyping of non-small cell lung cancer in cytologic material. Patients and methodsThis is a retrospective study including 40 cases of primary lung lesions who underwent image guided FNAC from pulmonary nodules. The final histopathologic diagnosis was the gold standard. Cell blocks were stained with anti-TTF-1, and P63. Nuclear immunoreactivity for both markers was considered specific. Sensitivity, specificity, positive and negative predictive values, of the cytologic diagnosis and of the two markers, as well as the accuracy of the combined markers were calculated. ResultsCytomorphology achieved a sensitivity of 83.3%, specificity of 91%, PPV of 91%, and NPV of 83.3%, for the diagnosis of AC, and 91% sensitivity, 83.3% specificity, 83.3% PPV, and 91% NPV, for the diagnosis of SCC. The concordance between cytologic and histopathologic diagnoses of AC and SCC was 87%. TTF-1 achieved 87.5% sensitivity, 94.7% specificity, 95.5% PPV, and 85.7% NPV for AC, while P63 achieved 94.7% sensitivity, 95.8% specificity, 94.7% PPV, and 95.8% NPV for SCC. TTF-1 enhanced the sensitivity of cytomorphology for AC from 83.3% to 87.5%, and specificity from 91% to 94.7%. Similarly P63 enhanced the sensitivity for SCC from 91% to 94.7%, and specificity from 83.3% to 95.8%. ConclusionTTF-1 achieved moderate sensitivity, and high specificity in the diagnosis of AC, while P63 was highly sensitive and specific for the diagnosis of SCC. Immunocytochemistry raised the sensitivity and specificity of FNAC in diagnosing AC and SCC using TTF-1 and P63, respectively.

TTF-1 Expression in Ovarian and Uterine Epithelial Neoplasia and its Potential Significance, an Immunohistochemical Assessment With Multiple Monoclonal Antibodies and Different Secondary Detection Systems

Thyroid transcription factor-1 (TTF-1) is a 38-kd homeodomain containing DNA-binding protein, identified in thyroid and lung as a regulator of thyroid-specific genes and surfactant and Clara cell secretory protein gene expression. TTF-1 has been used as a reliable lineage marker for lung adenocarcinoma and thyroid carcinoma in surgical pathology. However, TTF-1 expression has been recently reported in carcinomas of other origins including female genital tract. We evaluated TTF-1 expression with 3 primary different antibodies (8G7G3/1, SPT24, and BGX-397A) and 2 secondary automated detection systems (Envision+/Dako autostainer versus Refine/Bond Max) in 104 ovarian and endometrial tumors on routine surgical specimens and 108 ovarian tumors on tissue microarray (TMA) specimens. SPT24 and Refine/Bond Max autostainer was the most sensitive system among the primary antibodies and secondary detection/autostainers tested. By using SPT24/Refine/Bond Max, TTF-1 reactivity could be detected in all major histologic subtypes of gynecologic tumors and up to 26% of all cases tested on routine surgical specimens and 6.4% on TMA. TTF-1 was most frequently detected in uterine malignant mixed Müllerian tumor (82%), more common in uterine tumors than ovarian tumors, and more common in surgical specimen than TMA. When present, tumor cells can be rarely positive or diffusely positive for TTF-1 reactivity. In addition to malignant tumors, TTF-1 was also detected in benign tumors and benign tubal and endometrial epithelia. TTF 1 immunostaining has the potential to misguide a pathologist to conclude an ovarian or endometrial tumor being a lung metastasis. However, the role of TTF-1 in female genital tract and its tumors is unknown.

Thyroid transcription factor-1 exhibits osmosensitive transcription in brain-derived cell lines

Thyroid transcription factor-1 (TTF-1) belongs to the Nkx family of homeodomain-containing proteins and regulates expression of several important genes in the brain. Our previous studies showed that TTF-1 plays an important role in water homeostasis in the subfornical organ of rats and is involved in cerebrospinal fluid formation by regulation of aquaporin-1 transcription in the choroid plexus. In this study, we examined changes in TTF-1 transcription in response to hypertonicity using promoter assays. TTF-1 was synthesized in several osmosensitive regions of the rat brain. TTF-1 promoter activity was diminished by treatment with hypertonic solutions in a time- and dose-dependent manner in brain-derived cell lines. Additionally, TTF-1 was involved in the regulation of angiotensinogen (Aogen) transcription under a hyperosmotic condition through specific binding domains in the Aogen promoter. These results suggest a possible role of TTF-1 in brain fluid homeostasis in response to changes in the osmotic environment.

Prognostic role of thyroid transcription factor-1 in stage III non-small cell lung cancer

Stage III NSCLC represents a heterogeneous group and the ISS remains unsatisfactory in term of prognosis prediction. The aim of the present study was to determine the role of TTF-1 as prognostic factor in stage III NSCLC in addition to other known clinical factors. All stage III NSCLC patients treated in our hospital were retrieved and searched for biopsy specimens. TTF-1 was assessed by immunohistochemistry (Novocastra SPT24). Between 01/1987 and 07/2003, 108 assessable stage III NSCLC patients were included in the study. Their principal characteristics were: median age 64 years (range 37-83), male/female 81/27, squamous/non squamous 52/56, IIIA/IIIB 44/64, median Karnofsky PS 80 (range 20-100). Forty-four patients were positive for TTF-1 (squamous 25.0% versus non-squamous 55.4%). In multivariate analysis, only three factors were statistically significantly associated with better survival: good PS, surgery and creatinine level. In stage III NSCLC patients, good PS, resectability and low creatinine level but not TTF-1 are prognostic factors for survival.

Role Of TTF-1, CK20, And CK7 Immunohistochemistry for Diagnosis of Primary and Secondary Lung Adenocarcinoma

Thyroid transcription factor-1 (TTF-1), and cytokeratin 7 (CK7) and cytokeratin 20 (CK20) have recently been reported to be useful to distinguish between primary and metastatic lung adenocarcinoma. The aim of this study was to determine the usefulness of the staining patterns of pulmonary adenocarcinoma with antibodies to TTF-1, CK7, and CK20 in differentiating primary from metastatic pulmonary adenocarcinoma. Of the 66 lung adenocarcinoma specimens that were enrolled in our study, there were 40 primary lung adenocarcinomas, 12 metastatic adenocarcinomas from breast, 13 metastatic adenocarcinomas from colon, and 1 metastatic adenocarcinoma from stomach. The expression of TTF-1, CK7, and CK20 was assessed by immunohistochemistry. We found that 73% of primary lung adenocarcinomas expressed TTF-1, whereas all nonpulmonary adenocarcinomas lacked TTF-1 staining. CK7 expression was significantly more frequent in adenocarcinomas of pulmonary and breast origin than gastrointestinal (GI) origin (p < 0.001). In contrast, CK20 expression was significantly more prevalent in adenocarcinoma that originated in the GI tract than that of pulmonary or breast origin (p < 0.001). A combination of TTF-1+CK7+CK20- was highly significantly associated with primary adenocarcinoma of lung (vs GI tract, p < 0.001; vs breast, p < 0.001). A combination of TTF-1-CKCK20+ was highly significantly associated with adenocarcinoma of GI origin (vs lung, p < 0.001; vs breast, p < 0.001). Our study has confirmed that expression of CK7, CK20, and TTF-1 is a useful immunohistochemical marker for diagnosis of lung tumors and for differential diagnosis of primary pulmonary adenocarcinomas from extrapulmonary adenocarcinomas metastatic to the lung. Application of this panel of antibodies might be expected to increase the accuracy of diagnosis.

The role of TTF-1 in differentiating primary and metastatic lung adenocarcinomas.

Thyroid transcription factor-1 (TTF-1) is a sensitive marker for pulmonary and thyroid adenocarcinomas. The aim of this work was to determine its usefulness in distinction between primary and metastatic lung adenocarcinomas. We have examined the expression of TTF-1 in 100 solitary pulmonary nodules. They included 50 stage I peripheral primary bronchial adenocarcinomas (30 men, 20 women, mean age: 60 years) and 50 metastatic pulmonary adenocarcinomas (21 men, 29 women, mean age: 57 years) of different origins, such as breast (13), colon (13), rectum (13), kidney (7), stomach (2), and thyroid gland (2). TTF-1 immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissues. In primary bronchial adenocarcinomas we found immunopositivity in 46/50 cases, among them 30 cases showed strong nuclear immunostaining. In four primary adenocarcinoma cases the observed immunopositivity was localized to the cytoplasm. Out of the metastatic adenocarcinomas all but the 2 thyroid cancers were negative. Both thyroid tumors showed strong immunopositivity. Our results confirm that TTF-1 immunohistochemistry is a very sensitive and highly specific method in the differential diagnosis of primary and metastatic lung adenocarcinomas and should be used in the everyday clinical practice.

Phorbol Ester Down-regulation of Lung Surfactant Protein B Gene Expression by Cytoplasmic Trapping of Thyroid Transcription Factor-1 and Hepatocyte Nuclear Factor 3

The lung-specific surfactant protein B (SP-B) is essential for surfactant function and normal respiration. We investigated the role of thyroid transcription factor-1 (TTF-1) and hepatocyte nuclear factor 3 (HNF3) in the down-regulation of SP-B gene expression by phorbol ester in pulmonary adenocarcinoma H441 cells. Responsiveness to 12-O-tetradecanoylphorbol-13-acetate (TPA) localized to the SP-B proximal promoter (-140/-65 bp) and specifically to binding sites for TTF-1 and HNF3, which act as cell-specific enhancers of SP-B expression. Treatment of cells with TPA (10 nM) caused a time-dependent decrease in both TTF-1 and HNF3 in nuclear extracts and accumulation of both factors in the cytoplasm as assessed by electromobility shift, Western, Southwestern, and immunofluorescence assays. Treatment did not alter the mRNA content or DNA binding activity for either transcription factor. We conclude that down-regulation of SP-B gene expression by phorbol ester involves cytoplasmic trapping and loss of TTF-1 and HNF3 from the nucleus. This mechanism of action is independent of AP-1 and other transcription factors known to be influenced by phorbol ester.