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Thyroid transcription factor-2 (TTF2) is a nuclear protein involved in morphogenesis and gene expression in thyroid gland, belonging to the family of the forkhead/winged-helix transcription factors. In the present study we have investigated the sequence determinants for transport and accumulation into the nucleus of the TTF2 protein. By transient expression of fusion proteins constructed by joining different parts of TTF2 to the reporter gene of the jellyfish green fluorescent protein (GFP) and, in a separate set of deleted constructs, the glutathione S-transferase (GST) coding sequence, we have demonstrated that a basic amino acid stretch present at both ends of the DNA-binding domain is a bona fide nuclear localization signal (NLS). We have analyzed the subcellular localization of deleted GFP-GST-TTF2 fusion proteins and have shown that residues inside the forkhead domain (FHD) contributed to the complete nuclear TTF2 protein accumulation. Furthermore, by means of GST binding assays we have shown that distinct TTF2 fragments, containing the NLS, were able to bind the nuclear import receptor importin alpha. Taken together, our results provide the first documentation about nuclear targeting of a forkhead protein containing two identical NLS signal flanking the DNA-binding domain.
Background & Aims: Hepatocellular carcinoma (HCC) is among the leading causes of cancer deaths worldwide. Many studies indicate that disruption of cellular thyroid hormone signaling promotes HCC progression. However, the mechanisms underlying the regulation of genes downstream of thyroid hormone actions in HCC have remained elusive. In the current study, we identified NUPR1 (nuclear protein-1), a stress-induced protein that overexpresses in various neoplasia, is upregulated by triiodothyronine/thyroid hormone receptor (T3/TR) signaling and aimed to elucidate its role in angiogenesis in cancer progression. Methods: Quantitative reverse transcription-PCR, luciferase promoter and chromatin immunoprecipitation assays were performed to identify the NUPR1 regulatory mechanism by T3/TR. In vitro and In vivo vascular formations were performed to detect the angiogenic function of NUPR1. Human angiogenesis arrays were performed to identify the downstream angiogenic pathway. The sorafenib resistant ability of TR/NUPR1 was further examined in vitro and in vivo. Clinical relevance of TR, NUPR1 and platelet-derived growth factor A (PDGFA) were investigate in HCC samples using qRT-PCR and western blot. Results: Our experiments disclosed positive regulation of NUPR1 expression by T3/TR through direct binding to the -2066 to -1910 region of the NUPR1 promoter. Elevated NUPR1 and TR expression link to poor survival in clinical HCC specimens. An analysis of clinicopathological parameters showed that expression of NUPR1 is associated with vascular invasion and pathology stage. Functional studies revealed that NUPR1 induced endothelial cell angiogenesis in vitro and in vivo. Using a human angiogenesis array, we identified PDGFA as a target of NUPR1 in the downstream angiogenic pathway. NUPR1 induced transcription of PDGFA through direct binding to the corresponding promoter region, and inhibition of the PDGFA signaling pathway impaired angiogenesis in human umbilical vein endothelial cells (HUVECs). Notably, the angiogenic effects of NUPR1/PDGFA were mediated by the MEK/ERK signaling pathway. TR/NUPR1 expression increased cell viability and resistance to sorafenib treatment. Moreover NUPR1 expression was positively correlated with TRα, TRβ, and PDGFA expression. Conclusions: We propose that the T3/TR/NUPR1/PDGFA/MEK/ERK axis has a vital role in hepatocarcinogenesis and suggest NUPR1 as a potential therapeutic target in HCC.
Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is upregulated by hypoxia and oncogenic signalling in many solid tumours. Its regulation and function in thyroid carcinomas are unknown. We evaluated the regulation of HIF-1 alpha and target gene expression in primary thyroid carcinomas and thyroid carcinoma cell lines (BcPAP, WRO, FTC-133 and 8505c). HIF-1 alpha was not detectable in normal tissue but was expressed in thyroid carcinomas. Dedifferentiated anaplastic tumours (ATCs) exhibited high levels of nuclear HIF-1 alpha staining. The HIF-1 target glucose transporter 1 was expressed to a similar level in all tumour types, whereas carbonic anhydrase-9 was significantly elevated in ATCs. In vitro studies revealed a functionally active HIF-1 alpha pathway in thyroid cells with transcriptional activation observed after graded hypoxia (1% O(2), anoxia) or treatment with a hypoxia mimetic cobalt chloride. High basal and hypoxia-induced expression of HIF-1 alpha in FTC-133 cells that harbour a phosphatase and tensin homologue (PTEN) mutation was reduced by introduction of wild-type PTEN. Similarly, pharmacological inhibition of the phosphoinositide 3-kinase (PI3K) pathway using LY294002 inhibited HIF-1 alpha and HIF-1 alpha targets in all cell lines, including those with B-RAF mutations (BcPAP and 8505c). In contrast, the effects of inhibition of the RAF/MEK/extracellular signal-regulated kinase pathway were restricted by environmental condition and B-RAF mutation status. HIF-1 is functionally expressed in thyroid carcinomas and is regulated not only by hypoxia but also via growth factor signalling pathways and, in particular, the PI3K pathway. Given the strong association of HIF-1 alpha with an aggressive disease phenotype and therapeutic resistance, this pathway may be an attractive target for improved therapy in thyroid carcinomas.
In chronic kidney disease (CKD) patients, inflammation plays a pivotal role in the progression of renal fibrosis. Hypothyroidism is associated with an increased occurrence of atherosclerosis and inflammation, suggesting protective roles of thyroid hormones and their receptors against inflammatory processes. The contribution of thyroid hormone receptors to macrophage differentiation has not been well documented. Here, we focused on the endogenous thyroid hormone receptor α (TRα) in macrophages and examined the role of ligand-bound TRα in macrophage polarization-mediated anti-inflammatory effects. TRα-deficient irradiated chimeric mice showed exacerbated tubulointerstitial injury in a unilateral ureteral obstruction model. Compared with wild-type macrophages, macrophages isolated from the obstructed kidneys of mice lacking TRα displayed increased expression of proinflammatory cytokines that was accompanied by enhanced nuclear translocation of p65. Comparison of TRα-deficient bone marrow-derived macrophages with wild-type macrophages confirmed the propensity of the former cells to produce excessive IL-1β levels. Co-culture of these macrophages with renal epithelial cells induced more severe damage to the epithelial cells via the IL-1 receptor. Our findings indicate that ligand-bound TRα on macrophages plays a protective role in kidney inflammation through the inhibition of NF-κB pathways, possibly by affecting the pro- and anti-inflammatory balance that controls the development of CKD.
We investigated post-translational modification and subcellular localisation of endogenous platelet-derived growth factor-C (PDGF-C) in human thyroid papillary carcinomas (PTC), non-neoplastic thyroid tissues, and a selection of cultured cell lines. PDGF-C expressed nuclear localisation in 95% of all tested cell types in culture and in 10% of the thyrocytes from both PTC and non-neoplastic tissue. The cell lines expressed two forms of full-length PDGF-C, approximately 39 and approximately 55 kDa, in cell membrane and cytosol, while the approximately 55 kDa form dominated in the nucleus where it was partly chromatin-associated. The approximately 55 kDa form was post-translationally modified by SUMO-1. The putative PDGF-C SUMOylation site is the surface exposed (314)lysine part of a positively charged loop ((312)RPKTGVRGLHK(322)) with characteristics of a nuclear localisation signal. The tissue thyrocytes expressed a non-SUMOylated approximately 43 kDa and the 55 kDa PDGF-C. The SUMO-1 modified approximately 55 kDa PDGF-C expression was low in PTC where the approximately 43 kDa PDGF-C dominated. This is in contrast to non-neoplastic tissue and cultured cells where the SUMOylated approximately 55 kDa PDGF-C was strongly expressed. Our data provide novel evidence for nuclear localisation of PDGF-C, post-translational modification by SUMOylation and the expression of a novel form of PDGF-C in human papillary thyroid carcinomas.
BACKGROUND Papillary thyroid carcinoma (PTC) is associated with mutations of BRAFV600E and RET/PTC and high levels of expression of nuclear factor-κB (NF-κB). However, few studies have focused on the association between NF-κB expression and mutations in BRAFV600E and RET/PTC, especially regarding PTC cell proliferation and migration. The aim of this in vitro study was to investigate the effect of BRAFV600E or RET/PTC on NF-κB expression, cell proliferation and cell migration in four established PTC cell lines. MATERIAL AND METHODS Four cell lines included TPC-1 (BRAFWT/WT), BCPAP (BRAFV600E/V600E), PCCL3, and PTC3-5 (RET/PTC), were grown in culture in vitro with or without suppression of NF-κB using pyrrolidine dithiocarbamate (PDTC), and cell proliferation, and cell migration were evaluated. RESULTS Expression of the BRAF gene was increased in the BCPAP cell line when compared with the TPC-1 cells. Expression of the RET gene was increased in the PTC3-5 cell line when compared with the PCCL3 cells. In the BCPAP and PTC3-5 cell lines, the relative expression of NF-κB protein, including phosphorylated p100/52, phosphorylated p65, phosphorylated IKKa/b, phosphorylated IκBα, and p65 nuclear translocation were increased compared with the TPC-1 and PCCL3 cells. Proliferation and migration of BCPAP and PTC3-5 cells were increased compared with the TPC-1 and PCCL3 cells. Suppression of NF-κB reduced NF-κB protein expression and inhibited the proliferation of cells in the TPC-1, BCPAP, PCCL3 and PTC3-5 cell lines, and migration of the BCPAP and PTC3-5 cells. CONCLUSIONS BRAFV600E and RET/PTC and the expression of NF-κB promote the proliferation and migration of papillary thyroid carcinoma cells in vitro.
Thyroid hormone receptor (TR) is a member of the nuclear receptor superfamily that shuttles between the cytosol and nucleus. The fine balance between nuclear import and export of TR has emerged as a critical control point for modulating thyroid hormone-responsive gene expression; however, sequence motifs of TR that mediate shuttling are not fully defined. Here, we characterized multiple signals that direct TR shuttling. Along with the known nuclear localization signal in the hinge domain, we identified a novel nuclear localization signal in the A/B domain of thyroid hormone receptor α1 that is absent in thyroid hormone receptor β1 and inactive in the oncoprotein v-ErbA. Our prior studies showed that thyroid hormone receptor α1 exits the nucleus through two pathways, one dependent on the export factor CRM1 and the other CRM1-independent. Here, we identified three novel CRM1-independent nuclear export signal (NES) motifs in the ligand-binding domain as follows: a highly conserved NES in helix 12 (NES-H12) and two additional NES sequences spanning helix 3 and helix 6, respectively. Mutations predicted to disrupt the α-helical structure resulted in a significant decrease in NES-H12 activity. The high degree of conservation of helix 12 suggests that this region may function as a key NES in other nuclear receptors. Furthermore, our mutagenesis studies on NES-H12 suggest that altered shuttling of thyroid hormone receptor β1 may be a contributing factor in resistance to thyroid hormone syndrome. Taken together, our findings provide a detailed mechanistic understanding of the multiple signals that work together to regulate TR shuttling and transcriptional activity, and they provide important insights into nuclear receptor function in general.
Methylglyoxal (MG) is a potent inducer of advanced glycation end products (AGEs). MG, long considered a highly cytotoxic molecule with potential anticancer value, is now being re-evaluated to a protumorigenic agent in some malignancies. Anaplastic thyroid cancer (ATC) is an extremely aggressive and highly lethal cancer for which conventional therapies have proved ineffective. Successful therapeutic intervention in ATC is undermined by our poor understanding of its molecular etiology. In the attempt to understand the role of MG in ATC aggressiveness, we used immunohistochemistry to examine the level of MG protein adducts in ATC and slow-growing papillary thyroid cancer (PTC). We detected a high level of MG adducts in ATC compared to PTC ones, suggesting a protumor role for MG-mediated dicarbonyl stress in ATC. Accordingly, MG adduct accumulation in ATC cells in vitro was associated with a marked mesenchymal phenotype and increased migration/invasion, which were both reversed by aminoguanidine (AG)-a scavenger of MG-and resveratrol-an activator of Glyoxalase 1 (Glo1), the key metabolizing enzyme of MG. Our study represents the first demonstration that MG, via AGEs, acts as a tumor-promoting factor in ATC and suggests that MG scavengers and/or Glo1 activators merit investigations as potential therapeutic strategies for this malignancy.
The THRA gene, encoding the thyroid hormone nuclear receptor TRα1, is expressed in an increasing gradient at the bottom of intestinal crypts, overlapping with high Wnt and Notch activities. Importantly, THRA is upregulated in colorectal cancers, particularly in the high-Wnt molecular subtype. The basis of this specific and/or altered expression pattern has remained unknown. To define the mechanisms controlling THRA transcription and TRα1 expression, we used multiple in vitro and ex vivo approaches. Promoter analysis demonstrated that transcription factors important for crypt homeostasis and altered in colorectal cancers, such as transcription factor 7-like 2 (TCF7L2; Wnt pathway), recombining binding protein suppressor of hairless (RBPJ; Notch pathway), and homeobox protein CDX2 (epithelial cell identity), modulate THRA activity. Specifically, although TCF7L2 and CDX2 stimulated THRA, RBPJ induced its repression. In-depth analysis of the Wnt-dependent increase showed direct regulation of the THRA promoter in cells and of TRα1 expression in murine enteroids. Given our previous results on the control of the Wnt pathway by TRα1, our new results unveil a complex regulatory loop and synergy between these endocrine and epithelial-cell-intrinsic signals. Our work describes, for the first time, the regulation of the THRA gene in specific cell and tumor contexts.
Our previous work demonstrated a key function of the thyroid hormone nuclear receptor TRα1, a T3-modulated transcription factor, in controlling intestinal development and homeostasis via the Wnt and Notch pathways. Importantly, increased expression of TRα1 in the intestinal epithelium in a mutated Apc genetic background (vil-TRα1/Apc+/1638N mice) accelerated tumorigenesis and contributed to a more aggressive tumor phenotype compared to that of the Apc mutants alone. Therefore, the aim of this study was to determine the relevance of this synergistic effect in human colorectal cancers and to gain insights into the mechanisms involved. We analyzed cohorts of patients by in silico and experimental approaches and observed increased TRα1 expression and a significant correlation between TRα1 levels and Wnt activity. TRα1 loss-of-function and gain-of-function in Caco2 cell lines not only confirmed that TRα1 levels control Wnt activity but also demonstrated the role of TRα1 in regulating cell proliferation and migration. Finally, upon investigation of the molecular mechanisms responsible for the Wnt-TRα1 association, we described the repression by TRα1 of several Wnt inhibitors, including Frzb, Sox17 and Wif1. In conclusion, our results underline an important functional interplay between the thyroid hormone nuclear receptor TRα1 and the canonical Wnt pathway in intestinal cancer initiation and progression. More importantly, we show for the first time that the expression of TRα1 is induced in human colorectal cancers.
The tumor microenvironment (TME) and activated angiogenesis in thyroid carcinoma (TC) are critical for tumor growth and metastasis. Nuclear receptor binding protein 2 (NRBP2) has been suggested as a tumor suppressor. This study examines the function of NRBP2 in the progression of TC and the regulatory mechanism. By analyzing bioinformatic tools including GSE165724 dataset and the Cancer Genome Atlas system, we predicted NRBP2 as a poorly expressed gene in TC. Decreased NRBP2 expression was detected in TC tumor tissues and cells. Poor expression of NRBP2 was linked to unfavorable prognosis of patients. GATA binding protein 1 (GATA1) was found as a negative regulator of NRBP2. It recruited histone deacetylase2 (HDAC2) to the NRBP2 promoter to trigger histone deacetylation. NRBP2 overexpression suppressed growth of TC cells, and it reduced expression of TME markers, M2 polarization of macrophages, and angiogenesis in TC. Similar results were reproduced in vivo in nude mice. However, the anti-oncogenic roles of NRBP2 were blocked after further overexpression of GATA1 or HDAC2. In summary, this study demonstrates that GATA1 recruits HDAC2 to the NRBP2 promoter and enhances the TME and angiogenesis in TC cells.
L-3,3',5-triiodothyronine (T(3)) administration upregulates nuclear factor-E2-related factor 2 (Nrf2) in rat liver, which is redox-sensitive transcription factor mediating cytoprotection. In this work, we studied the role of Kupffer cell respiratory burst activity, a process related to reactive oxygen species generation and liver homeostasis, in Nrf2 activation using the macrophage inactivator gadolinium chloride (GdCl(3); 10 mg/kg i.v. 72 h before T(3) [0.1 mg/kg i.p.]) or NADPH oxidase inhibitor apocynin (1.5 mmol/L added to the drinking water for 7 days before T(3)), and determinations were performed 2 h after T(3). T(3) increased nuclear/cytosolic Nrf2 content ratio and levels of heme oxygenase 1 (HO-1), catalytic subunit of glutamate cysteine ligase, and thioredoxin (Western blot) over control values, proteins whose gene transcription is induced by Nrf2. These changes were suppressed by GdCl(3) treatment prior to T(3), an agent-eliciting Kupffer-cell depletion, inhibition of colloidal carbon phagocytosis, and the associated respiratory burst activity, with enhancement in nuclear inhibitor of Nrf2 kelch-like ECH-associated protein 1 (Keap1)/Nrf2 content ratios suggesting Nrf2 degradation. Under these conditions, T(3)-induced tumor necrosis factor-α (TNF-α) response was eliminated by previous GdCl(3) administration. Similar to GdCl(3), apocynin given before T(3) significantly reduced liver Nrf2 activation and HO-1 expression, a NADPH oxidase inhibitor eliciting abolishment of colloidal carbon-induced respiratory burst activity without altering carbon phagocytosis. It is concluded that Kupffer cell functioning is essential for upregulation of liver Nrf2-signaling pathway by T(3). This contention is supported by suppression of the respiratory burst activity of Kupffer cells and the associated reactive oxygen species production by GdCl(3) or apocynin given prior to T(3), thus hindering Nrf2 activation.
The aim of this study was to investigate the expression of thyroid hormone receptor β1 (THRβ1) by immunohistochemistry in breast cancer (BC) tissues and to correlate the results with clinico-biological parameters. In a well-characterized cohort of 274 primary BC patients, THRβ1 was widely expressed with a predominant nuclear location, although cytoplasmic staining was also frequently observed. Both nuclear and cytoplasmic THRβ1 were correlated with high-risk BC markers such as human epidermal growth factor receptor 2 (HER2), Ki67 (also known as MKI67), prominin-1 (CD133), and N-cadherin. Overall survival analysis demonstrated that cytoplasmic THRβ1 was correlated with favourable survival (p = 0.015), whereas nuclear THRβ1 had a statistically significant correlation with poor outcome (p = 0.038). Interestingly, in our cohort, nuclear and cytoplasmic THRβ1 appeared to be independent markers either for poor (p = 0.0004) or for good (p = 0.048) prognosis, respectively. Altogether, these data indicate that the subcellular expression of THRβ1 may play an important role in oncogenesis. Moreover, the expression of nuclear THRβ1 is a negative outcome marker, which may help to identify high-risk BC subgroups.
Papillary thyroid carcinomas (PTCs) have an excellent prognosis, but a fraction of them show aggressive behavior, becoming radioiodine (RAI)-resistant and/or metastatic. AXL (Anexelekto) is a tyrosine kinase receptor regulating viability, invasiveness and chemoresistance in various human cancers, including PTCs. Here, we analyze the role of AXL in PTC prognosis and as a marker of RAI refractoriness. Immunohistochemistry was used to assess AXL positivity in a cohort of human PTC samples. Normal and cancerous thyroid cell lines were used in vitro for signaling, survival and RAI uptake evaluations. 38.2% of human PTCs displayed high expression of AXL that positively correlated with RAI-refractoriness and disease persistence or recurrence, especially when combined with v-raf murine sarcoma viral oncogene homolog B(BRAF) V600E mutation. In human PTC samples, AXL expression correlated with V-akt murine thymoma viral oncogene homolog 1 (AKT1) and p65 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation levels. Consistently, AXL stimulation with its ligand growth arrest-specific gene 6 (GAS6) increased AKT1- and p65 NF-kB-phosphorylation and promoted survival of thyroid cancer cell lines in culture. Enforced expression or activation of AXL in normal rat thyroid cells significantly reduced the expression of the sodium/iodide symporter (NIS) and the radioiodine uptake. These data indicate that AXL expression levels could be used as predictor of RAI refractoriness and as a possible novel therapeutic target of RAI resistant PTCs.
Thyrotropin receptor (TSH-R), thyroglobulin (Tg), thyroperoxidase (TPO), thyroid specific transcription factor-1 (TTF-1), paired box 8 transcription factor (PAX-8), insulin like growth factor-1 (IGF-1) and estrogen receptor alpha (ERα) transcripts were determined by real-time PCR in follicular carcinoma and contralateral (CL) lobes, and healthy thyroid canine glands. Concentrations of TSH-R, PAX-8, and ERα mRNA were not different among groups; the carcinoma group had lower Tg and TPO mRNA than healthy and CL groups, while no differences were found between the two latter groups, suggesting that the carcinoma tissue presents an altered capacity to synthesize thyroid hormones. The transcription factor that promotes thyrocytes proliferation, TTF-1 as well as IGF-1, presented a greater mRNA expression in the CL group, suggesting that the CL lobe may function in a compensatory state.
The aim of the present study was to investigate the expression and localization of nuclear factor erythroid 2-related factor 2 (Nrf2) in the ovaries of mice in different age groups, and to explore the association between Nrf2 and premature ovarian aging. The present study identified the localization of Nrf2 protein by performing immunohistochemical assay of ovarian tissues obtained from mice in different age groups. The mRNA expression levels of Nrf2 were detected via reverse transcription-quantitative polymerase chain reaction, while the expression levels of Nrf2 protein and apoptosis-associated proteins, including Caspase3 and B-cell lymphoma 2 (Bcl-2), were evaluated by western blot analysis. The results revealed that Nrf2 protein was mainly localized in granulosa cells, as well as in the secondary follicles and antral follicles of oocytes. Nrf2 expression levels were significantly lower in mice aged 4 days compared with 12-week-old mice (P<0.05), and the level of Nrf2 was lower in mice aged 40 weeks compared with those aged 12 weeks (P<0.05). In addition, the expression of the apoptosis protein Caspase3 in the ovarian tissue of mice aged 3, 8 and 12 weeks remained markedly greater when compared with those aged 4 days and 40 weeks. Bcl-2, an anti-apoptotic protein, was also significantly expressed in the ovarian tissues of juvenile (4-day-old) mice when compared with mice aged >40 weeks (P<0.05). In conclusion, Nrf2 was highly expressed in the ovarian tissues of mice of childbearing age (8-12 weeks old) and may possibly be involved in ovarian regulatory functions. The results indicated that Nrf2 expression and localization may have important implications in the prevention of ovarian aging.
Astrocyte elevated gene-1 (AEG-1), known as an oncogene, is overexpressed in various cancers and implicated in tumor progression and metastasis. However, its functional significance and underlying molecular mechanisms in thyroid cancer remain to be elucidated. In the present study, we detected the potential function of AEG-1 in papillary thyroid cancer (PTC). We also investigated the relation between AEG-1 and matrix metalloproteases (MMP)2 and 9 through immunohistochemistry, western blotting, real-time PCR, immunofluorescence staining, zymography and co-immunoprecipitation (Co-IP). We found that overexpression of AEG-1 in PTC was positively correlated with lymph node metastasis and MMP2/9 expression. Knockdown of AEG-1 reduced the capacity of migration and invasion through downregulation of MMP2/9 in thyroid cancer cells. Furthermore, we firstly found that AEG-1 interacted with MMP9 in thyroid cancer cells. AEG-1 was associated with the activation of the nuclear factor κB (NF-κB) signaling pathways in thyroid cancer cells. Overall, our results for the first time showed that AEG-1 interacted with MMP9 in thyroid cancer cells and AEG-1 expression was closely associated with progression and metastasis of papillary thyroid cancer. AEG-1 might be a potential therapeutic target in papillary thyroid cancer.
Thyroid cancer is the most common endocrine cancer, and has a high incidence of lymphatic metastasis. Vascular endothelial growth factor C (VEGFC) is essential for development of lymphatic vessels and lymphatic metastases during carcinogenesis. Steroid receptor coactivator-1 (SRC-1) interacts with nuclear receptors and transcription factors to promote tumor proliferation and metastasis. However, the correlation between SRC-1 and VEGFC levels in the lymphatic metastases of thyroid cancer remains unclear. We analyzed 20-paired specimens of thyroid cancer tissue and normal thyroid tissue and found increased levels of SRC-1 and VEGFC proteins in 13/20 and 15/20 thyroid cancer specimens, respectively, when compared with those levels in specimens of normal thyroid tissue. A high level of SRC-1 expression was positively correlated with VEGFC and lymphatic endothelial cell marker LYVE-1 expression. Papillary thyroid carcinoma cell line TPC-1 displayed high levels of SRC-1 and VEGFC expression and was selected for stable knockdown of SRC-1 in vitro Inhibition of SRC-1 significantly reduced the VEGFC levels in TPC-1 cells. We found that SRC-1 binds to transcription factor NF-kB (p50/p65), and that this coactivation complex directly promoted VEGFC transcription, which could be abrogated by SRC-1 knockdown. Up-regulated NF-kB signaling was also confirmed in thyroid cancer tissues. In vivo studies showed that SRC-1 knockdown restricted tumor growth, reduced the numbers of LYVE-1-positive lymphatic vessels, and decreased the levels of VEGFC in tumor tissues. These results suggest a tumorigenic role for SRC-1 in thyroid cancer via its ability to regulate VEGFC expression.
The occurrence of worsening pulmonary function has been connected to hypothyroidism (HPO). Hesperidin (HES) was suggested to have antioxidant, anti-proliferative, and anti-inflammatory potential. Our study's objective was to determine whether HES could reduce carbimazole (CBZ)-induced lung injury more effectively than Eltroxin (ELT) in adult male albino rats or not. At random, 32 rats were distributed into four groups: Group I: normal control, to induce HPO, the remaining three groups were given CBZ (20 mg/kg/day) dissolved in distilled water for 1 week. They were then split up into three groups. Group II: orally administered CBZ (20 mg/kg b.w in water/day), Group III: HES (200 mg/kg/day) dissolved in 1% carboxymethyl-cellulose + CBZ treated, and Group IV: ELT (0.045 mg/kg/day) dissolved in distilled water + CBZ treated. All treatments were delivered for 12 weeks. Blood was collected to assess thyroid-stimulating hormone (TSH) and thyroid hormones (THs). Lung injury was evaluated based on the pulmonary content of interleukin (IL)-35, IL-6, and tumor necrosis factor-alpha (TNF-α), along with the estimation of lipid peroxidation, catalase, glutathione levels, superoxide dismutase, heme oxygenase-1 (HO-1), and nuclear factor erythroid 2-related factor 2 (Nrf2). The histological, ultrastructural, and immunohistochemical study of nuclear factor Kappa-B (NF-κB) and inducible nitric oxide synthase (iNOS), together with estimating the proliferation of cells using Antigen Ki-67 in lung tissue were performed. HES and ELT primarily suppressed variable lung damage mechanisms by suppressing TSH, the NF-κB/TNF-α pathway, iNOS, lipid peroxidation, Ki-67, and inflammatory mediators. On the other hand, they improved THs, antioxidant parameters, and the Nrf2/HO-1 pathway. HES and ELT exhibited an ameliorative effect that was reflected in the histopathological, immunohistochemical, and ultrastructural results. These results indicate that HES is a pneumoprotective agent that could be a promising treatment for oxidative stress, inflammation, and proliferation.
CD40, a tumor necrosis factor receptor, is a major immune-modulating susceptibility gene for Graves disease (GD) as well as for a variety of other autoimmune diseases. Its broad association with autoimmunity underscores its paramount role in the development of a normal adaptive immune response, primarily in coordinating effective antigen presentation. The molecular pathways by which CD40 activation in the thyroid induces GD are unknown. In this study, we investigated whether NF-κB, a ubiquitious family of transcription factors, mediates the downstream effects of thyroid-specific CD40 activation. Cultured primary human thyrocytes, from patients with and without GD, underwent CD40 stimulation. Once stimulated, cytokines and transcription factors specific for either the canonical nuclear factor κB (NF-κB)1 pathway [interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α], which primarily recruits cells for innate immunity, or the noncanonical NF-κB2 pathway [B cell-activating factor of the TNF family, CC chemokine ligand (CCL)21], which directs B cell viability, were analyzed. Significant upregulation in the messenger RNA and protein levels of both canonical and noncanonical pathway cytokines was observed. Western blot analyses of the specific transcription factors for the NF-κB1 and NF-κB2 pathways (p65 and p100/p52, respectively) demonstrated that p65 is constitutively expressed. In contrast, CD40 stimulation robustly increased the expression of the NF-κB2 p52 transcription factor, and the upregulation was significantly more profound in the GD tissue than in the normal thyroid tissue. Our data show that CD40 activity in thyrocytes is prominently mediated via NF-κB and furthermore suggest that the NF-κB1 and NF-κB2 pathways both contribute to the triggering and the progression of GD.
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