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At least 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

Inhibition of BRD4 suppresses tumor growth and enhances iodine uptake in thyroid cancer

Thyroid cancer is a common malignancy of the endocrine system. Although radioiodine {sup 131}I treatment on differentiated thyroid cancer is widely used, many patients still fail to benefit from {sup 131}I therapy. Therefore, exploration of novel targeted therapies to suppress tumor growth and improve radioiodine uptake remains necessary. Bromodomain-containing protein 4 (BRD4) is an important member of the bromodomain and extra terminal domain family that influences transcription of downstream genes by binding to acetylated histones. In the present study, we found that BRD4 was up-regulated in thyroid cancer tissues and cell lines. Inhibition of BRD4 in thyroid cancer cells by JQ1 resulted in cell cycle arrest at G0/G1 phase and enhanced {sup 131}I uptake in vitro and suppressed tumor growth in vivo. Moreover, JQ1 treatment suppressed C-MYC but enhanced NIS expression. We further demonstrated that BRD4 was enriched in the promoter region of C-MYC, which could be markedly blocked by JQ1 treatment. In conclusion, our findings revealed that the aberrant expression of BRD4 in thyroid cancer is possibly involved in tumor progression, and JQ1 is potentially an effective chemotherapeutic agent against human thyroid cancer. - Highlights: • BRD4 is upregulated in thyroid cancer tissues and cell lines. • Inhibition of BRD4 induced cell cycle arrest and enhanced radioiodine uptake in vitro and impaired tumor growth in vivo. • JQ1 suppressed the expression of C-MYC and promoted the expression of NIS and P21. • JQ1 attenuated the recruitment of BRD4 to MYC promoter in thyroid cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

CHIP promotes thyroid cancer proliferation via activation of the MAPK and AKT pathways

The carboxyl terminus of Hsp70-interacting protein (CHIP) is a U box-type ubiquitin ligase that plays crucial roles in various biological processes, including tumor progression. To date, the functional mechanism of CHIP in thyroid cancer remains unknown. Here, we obtained evidence of upregulation of CHIP in thyroid cancer tissues and cell lines. CHIP overexpression markedly enhanced thyroid cancer cell viability and colony formation in vitro and accelerated tumor growth in vivo. Conversely, CHIP knockdown impaired cell proliferation and tumor growth. Notably, CHIP promoted cell growth through activation of MAPK and AKT pathways, subsequently decreasing p27 and increasing cyclin D1 and p-FOXO3a expression. Our findings collectively indicate that CHIP functions as an oncogene in thyroid cancer, and is therefore a potential therapeutic target for this disease. - Highlights: • CHIP is significantly upregulated in thyroid cancer cells. • Overexpression of CHIP facilitates proliferation and tumorigenesis of thyroid cancer cells. • Silencing of CHIP inhibits the proliferation and tumorigenesis of thyroid cancer cells. • CHIP promotes thyroid cancer cell proliferation via activating the MAPK and AKT pathways.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

MREG suppresses thyroid cancer cell invasion and proliferation by inhibiting Akt-mTOR signaling

Thyroid cancer has long been considered to arise in middle age and progress to more aggressive and lethal cancers after its repeated proliferation. In this research, we aimed at investigating the biological function and the underlying molecular mechanism of Melanoregulin (MREG) in thyroid cancer. It was found that the expression of MREG was significantly downregulated in thyroid cancer tissues. The downregulation of MREG expression was caused by epigenetic methylation. MREG overexpression could suppress the invasion and proliferation of thyroid cancer cells. While MREG knockdown promoted the invasion and proliferation of thyroid cancer cells. Furthermore, the phosphorylation of Akt or mTOR was decreased by MREG overexpression and increased by MREG knockdown. Moreover, Dactolisib (the inhibitor of mTOR) could abrogate silenced MREG induced thyroid cancer cell invasion and proliferation. Taken together, MREG regulates thyroid cancer cell invasion and proliferation through PI3K/Akt-mTOR signaling pathway. MREG may serve as a promising therapeutic strategy for thyroid cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Exposure to pyrethroids insecticides and serum levels of thyroid-related measures in pregnant women

Possible association between environmental exposure to pyrethroid insecticides and serum thyroid-related measures was explored in 231 pregnant women of 10–12 gestational weeks recruited at a university hospital in Tokyo during 2009–2011. Serum levels of free thyroxine (fT4), thyroid stimulating hormone (TSH) and thyroid biding globulin (TBG) and urinary pyrethroid insecticide metabolite (3-phenoxybenzoic acid, 3-PBA) were measured. Obstetrical information was obtained from medical records and dietary and lifestyle information was collected by self-administered questionnaire. Geometric mean concentration of creatinine-adjusted urinary 3-PBA was 0.363 (geometric standard deviation: 3.06) μg/g cre, which was consistent with the previously reported levels for non-exposed Japanese adult females. The range of serum fT4, TSH and TBG level was 0.83–3.41 ng/dL, 0.01–27.4 μIU/mL and 16.4–54.4 μg/mL, respectively. Multiple regression analysis was carried out by using either one of serum levels of thyroid-related measures as a dependent variable and urinary 3-PBA as well as other potential covariates (age, pre-pregnancy BMI, parity, urinary iodine, smoking and drinking status) as independent variables: 3-PBA was not found as a significant predictor of serum level of thyroid-related measures. Lack of association may be due to lower pyrethroid insecticide exposure level of the present subjects. Taking the ability of pyrethroid insecticides and their metabolite to bind to nuclear thyroid hormone (TH) receptor, as well as their ability of placental transfer, into consideration, it is warranted to investigate if pyrethroid pesticides do not have any effect on TH actions in fetus brain even though maternal circulating TH level is not affected. -- Highlights: • Pyrethroid exposure and thyroid hormone status was examined in pregnant women. • Urinary 3-phenoxybenzoic acid was used as a biomarker of exposure. • Iodine nutrition, age and other covariates were included in statistical models. • No association was found between levels of thyroid hormone and pyrethroid exposure. • The result may be ascribed to lower exposure level.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2016

Free Thyroid Transfer: A Novel Procedure to Prevent Radiation-induced Hypothyroidism

Purpose: The incidence of hypothyroidism after radiation therapy for head and neck cancer (HNC) has been found to be ≤53%. Medical treatment of hypothyroidism can be costly and difficult to titrate. The aim of the present study was to assess the feasibility of free thyroid transfer as a strategy for the prevention of radiation-induced damage to the thyroid gland during radiation therapy for HNC. Methods and Materials: A prospective feasibility study was performed involving 10 patients with a new diagnosis of advanced HNC undergoing ablative surgery, radial forearm free-tissue transfer reconstruction, and postoperative adjuvant radiation therapy. During the neck dissection, hemithyroid dissection was completed with preservation of the thyroid arterial and venous supply for implantation into the donor forearm site. All patients underwent a diagnostic thyroid technetium scan 6 weeks and 12 months postoperatively to examine the functional integrity of the transferred thyroid tissue. Results: Free thyroid transfer was executed in 9 of the 10 recruited patients with advanced HNC. The postoperative technetium scans demonstrated strong uptake of technetium at the forearm donor site at 6 weeks and 12 months for all 9 of the transplanted patients. Conclusions: The thyroid gland can be transferred as a microvascular free transfer with maintenance of function. This technique could represent a novel strategy for maintenance of thyroid function after head and neck irradiation.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Estimation of iodine nutrition and thyroid function status in late-gestation pregnant women in the United States: Development and application of a population-based pregnancy model

Previously, a deterministic biologically-based dose-response (BBDR) pregnancy model was developed to evaluate moderate thyroid axis disturbances with and without thyroid-active chemical exposure in a near-term pregnant woman and fetus. In the current study, the existing BBDR model was adapted to include a wider functional range of iodine nutrition, including more severe iodine deficiency conditions, and to incorporate empirically the effects of homeostatic mechanisms. The extended model was further developed into a population-based model and was constructed using a Monte Carlo-based probabilistic framework. In order to characterize total (T4) and free (fT4) thyroxine levels for a given iodine status at the population-level, the distribution of iodine intake for late-gestation pregnant women in the U.S was reconstructed using various reverse dosimetry methods and available biomonitoring data. The range of median (mean) iodine intake values resulting from three different methods of reverse dosimetry tested was 196.5–219.9 μg of iodine/day (228.2–392.9 μg of iodine/day). There was minimal variation in model-predicted maternal serum T4 and ft4 thyroxine levels from use of the three reconstructed distributions of iodine intake; the range of geometric mean for T4 and fT4, was 138–151.7 nmol/L and 7.9–8.7 pmol/L, respectively. The average value of the ratio of the 97.5th percentile to the 2.5th percentile equaled 3.1 and agreed well with similar estimates from recent observations in third-trimester pregnant women in the U.S. In addition, the reconstructed distributions of iodine intake allowed us to estimate nutrient inadequacy for late-gestation pregnant women in the U.S. via the probability approach. The prevalence of iodine inadequacy for third-trimester pregnant women in the U.S. was estimated to be between 21% and 44%. Taken together, the current work provides an improved tool for evaluating iodine nutritional status and the corresponding thyroid function status in pregnant women in the U.S. This model enables future assessments of the relevant risk of thyroid hormone level perturbations due to exposure to thyroid-active chemicals at the population-level. - Highlights: • A population-based thyroid function model for pregnant women was developed. • The model was used specifically study the late-gestation pregnant women in the U.S. • The prevalence of iodine inadequacy was estimated in the sub-population studied. • Developed model well predicts trimester-specific thyroid hormone reference ranges. • The model can be further used to study thyroid perturbations at a population level.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Low thyroid function is not associated with an accelerated deterioration in renal function

Abstract Background Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups. Methods Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models. Results A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) −4.07 (−6.37 to −1.78) and −2.40 (−3.78 to −1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50–4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function. Conclusions Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.

Meuwese, Christiaan L.↗
DOE OSTI2023

The Cross-sectional and Longitudinal Association Between Thyroid Function and Depression: A Population-Based Study

Abstract Context An association of thyroid function with mood disorders has been widely suggested, but very few studies have examined this association longitudinally. Objective We assessed the cross-sectional and longitudinal association between thyroid function and depression in a population-based cohort. Methods A total of 9471 individuals were included in cross-sectional analyses, of whom 8366 had longitudinal data. At baseline, we assessed thyroid function using serum samples (thyrotropin [TSH], free thyroxine (FT4), and thyroid peroxidase antibodies) and depressive symptoms using the Centre for Epidemiologic Studies Depression (CES-D) scale. Incident depressive events (n = 1366) were continuously followed up with the CES-D and clinical interviews. We analyzed the cross-sectional association of thyroid function and thyroid disease with depressive symptoms using linear and logistic regression, and the longitudinal association with Cox proportional hazard models for depressive events. Results Lower TSH levels and lower and higher FT4 levels were cross-sectionally associated with more depressive symptoms with a B value of −0.07 per 1 unit increase of natural log-transformed TSH (95% CI −0.11; −0.04). Furthermore, hypothyroidism was cross-sectionally associated with less depressive symptoms and hyperthyroidism with more depressive symptoms. Longitudinally, there was a U-shaped association between FT4 and incident depressive events but only in euthyroid participants. Conclusion We show a cross-sectional association between thyroid (dys)function with depressive symptoms, and a U-shaped association between FT4 and incident depressive events in euthyroid individuals. Our findings suggest an association of thyroid function with the risk of developing depression, albeit small. Reverse causation and additional underlying factors may also contribute to the association.

Roa Dueñas, Oscar Hernando (ORCID:0000000207522261↗
DOE OSTI2015

Inhibition of miR-146b expression increases radioiodine-sensitivity in poorly differential thyroid carcinoma via positively regulating NIS expression

Dedifferentiated thyroid carcinoma (DTC) with the loss of radioiodine uptake (RAIU) is often observed in clinical practice under radioiodine therapy, indicating the challenge for poor prognosis. MicroRNA (miRNA) has emerged as a promising therapeutic target in many diseases; yet, the role of miRNAs in RAIU has not been generally investigated. Based on recent studies about miRNA expression in papillary or follicular thyroid carcinomas, the expression profiles of several thyroid relative miRNAs were investigated in one DTC cell line, derived from normal DTC cells by radioiodine treatment. The top candidate miR-146b, with the most significant overexpression profiles in dedifferentiated cells, was picked up. Further research found that miR-146b could be negatively regulated by histone deacetylase 3 (HDAC3) in normal cells, indicating the correlation between miR-146b and Na{sup +}/I{sup −} symporter (NIS)-mediated RAIU. Fortunately, it was confirmed that miR-146b could regulate NIS expression/activity; what is more important, miR-146b interference would contribute to the recovery of radioiodine-sensitivity in dedifferentiated cells via positively regulating NIS. In the present study, it was concluded that NIS-mediated RAIU could be modulated by miR-146b; accordingly, miR-146b might serve as one of targets to enhance efficacy of radioactive therapy against poorly differential thyroid carcinoma (PDTC). - Highlights: • Significant upregulated miR-146b was picked up from thyroid relative miRNAs in DTC. • MiR-146b was negatively regulated by HDAC3 in normal thyroid carcinoma cells. • NIS activity and expression could be regulated by miR-146b in thyroid carcinoma. • MiR-146b inhibition could recover the decreased radioiodine-sensitivity of DTC cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Subpopulations of cancer stem cells found in papillary thyroid carcinoma

Highlights: • Papillary thyroid carcinoma primary cell culture derived spheres behave as cancer stem cells. • Depletion of ALDH{sup +} sphere cells does not eradicate papillary thyroid carcinoma. • ALDH{sup -} sphere cells can also function independently as thyroid carcinoma cancer stem cells. • ALDH{sup -} and ALDH{sup +} sphere cells coordinate in thyroid cancer initiation and progression. • Targeting both ALDH{sup +} and ALDH{sup -} cancer stem cells may effectively treat thyroid cancer. Papillary thyroid carcinoma (PTC) is the most common form of thyroid cancer and while it has a generally good prognosis, tumor recurrence remains a major clinical challenge. Studying laboratory cell lines as well as clinical specimens indicate that PTC may follow the cancer stem cell (CSC) model. However, CSC characteristics relevant in PTC initiation and progression remain largely unknown. Here we studied a population of sphere-growing tumor cells isolated from primary cultures of clinical PTC. These sphere-growing cells consisted of aldehyde dehydrogenase positive (ALDH{sup +}) and ALDH negative (ALDH{sup -}) cell subpopulations and demonstrated a hierarchical pattern of cell division. Using combinations of selective depletion, specific inhibition and cell sorting, we found that both subpopulations of the sphere cells were able to self-renew and initiate xenograft tumors independently, and fulfilled the definition of CSC. Importantly, when the subpopulations functioned together, the cancer-initiation efficiency and the xenograft tumor progression were significantly enhanced compared to either subpopulation alone. These data revealed crucial roles of ALDH{sup -} CSC in PTC biology and suggested that CSC subpopulations function cooperatively to control PTC initiation and progression. Together, our study indicates that CSC subpopulations isolated from clinical specimens offer unprecedented opportunities for investigating PTC pathogenesis and developing effective therapies.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2002

AmphiFoxE4, an amphioxus winged helix/forkhead gene encoding a protein closely related to vertebrate thyroid transcription factor-2: expression during pharyngeal development

The full-length sequence and developmental expression of amphioxus AmphiFoxE4 are described. Transcripts of the gene are first detected in the pharyngeal endoderm, where the club-shaped gland is forming and subsequently in the definitive gland itself. AmphiFoxE4 is closely related to vertebrate genes encoding the thyroid-specific transcription factor-2 (TTF2), which plays an early developmental role in the morphogenesis of the thyroid gland and a later role in hormone-mediated control of thyroid function. In amphioxus, AmphiFoxE4 expression is not thyroid specific because the club-shaped gland, the only structure expressing the gene, is not homologous to the vertebrate thyroid; instead, the thyroid homologue of amphioxus is a specialized region of the pharyngeal endoderm called the endostyle. We propose that (a) the pharynx of an amphioxus-like ancestor of the vertebrates included a club-shaped gland that expressed FoxE4 as well as an endostyle that did not, and (b) the club-shaped gland soon disappeared in the vertebrate line of descent but (c) not before there was a homeogenetic transfer of FoxE4 expression from the club-shaped gland to the nearby endostyle. Such a transfer could have provided part of the genetic program enabling the endostyle to separate from the pharyngeal endoderm and migrate away as the rudiment of the thyroid gland.

Non-NASA Center↗
DOE OSTI2018

A nested case-control study of polychlorinated biphenyls, organochlorine pesticides, and thyroid cancer in the Janus Serum Bank cohort

Highlights: • First study of pre-diagnostic organochlorine compounds in serum and thyroid cancer. • p,p′-DDE (DDT metabolite) inversely associated with thyroid cancer. • Birth cohort may be an effect modifier. • Some PCBs associated with thyroid cancer in youngest birth cohort. • Chlordane metabolites associated with thyroid cancer in youngest birth cohort. Polychlorinated biphenyls (PCBs) and organochlorine pesticides have been associated with altered thyroid hormone levels in humans, but their relationship with thyroid cancer is unknown.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2014

Soy isoflavones interfere with thyroid hormone homeostasis in orchidectomized middle-aged rats

We previously reported that genistein (G) and daidzein (D) administered subcutaneously (10 mg/kg) induce changes in the angio-follicular units of the thyroid gland, reduce concentration of total thyroid hormones (TH) and increase thyrotropin (TSH) in serum of orchidectomized middle-aged (16-month-old) rats. To further investigate these effects, we now examined expression levels of the thyroglobulin (Tg), thyroperoxidase (Tpo), vascular endothelial growth factor A (Vegfa) and deiodinase type 1 (Dio 1) genes in the thyroid; in the pituitary, genes involved in TH feedback control (Tsh β, Dio 1, Dio 2, Trh receptor); and in the liver and kidney, expression of T{sub 3}-activated genes Dio 1 and Spot 14, as well as transthyretin (Ttr), by quantitative real-time PCR. We also analyzed TPO-immunopositivity and immunofluorescence of T{sub 4} bound to Tg, determined thyroid T{sub 4} levels and measured deiodinase enzyme activities in examined organs. Decreased expression of Tg and Tpo genes (p < 0.05) correlated with immunohistochemical staining results, and together with decreased serum total T{sub 4} levels, indicates decreased Tg and TH synthesis following treatments with both isoflavones. However, expression of Spot 14 (p < 0.05) gene in liver and kidney was up-regulated, and liver Dio 1 expression and activity (p < 0.05) increased. At the level of pituitary, no significant change in gene expression levels, or Dio 1 and 2 enzyme activities was observed. In conclusion, both G and D impaired Tg and TH synthesis, but at the same time increased tissue availability of TH in peripheral tissues of Orx middle-aged rats. - Highlights: • We tested how genistein and daidzein interfere with thyroid hormone homeostasis. • Thyroid: decreased expression of Tg and TPO genes correlated with IHC results. • Serum: total T{sub 4} reduced and TSH increased. • Liver and kidney: expression of Spot 14 and liver Dio 1 activity increased. • Pituitary: expression of T{sub 3}-regulated genes and Dio 1 and 2 activities unchanged.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Non-thyroid cancer incidence in Belarusian residents exposed to Chernobyl fallout in childhood and adolescence: Standardized Incidence Ratio analysis, 1997–2011

Background: While an increased risk of thyroid cancer from post-Chernobyl exposure to Iodine-131 (I-131) in children and adolescents has been well-documented, risks of other cancers or leukemia as a result of residence in radioactively contaminated areas remain uncertain. Methods: We studied non-thyroid cancer incidence in a cohort of about 12,000 individuals from Belarus exposed under age of 18 years to Chernobyl fallout (median age at the time of Chernobyl accident of 7.9 years). During 15 years of follow-up from1997 through 2011, 54 incident cancers excluding thyroid were identified in the study cohort with 142,968 person-years at risk. We performed Standardized Incidence Ratio (SIR) analysis of all solid cancers excluding thyroid (n=42), of leukemia (n=6) and of lymphoma (n=6). Results: We found no significant increase in the incidence of non-thyroid solid cancer (SIR=0.83, 95% Confidence Interval [CI]: 0.61; 1.11), lymphoma (SIR=0.66, 95% CI: 0.26; 1.33) or leukemia (SIR=1.78, 95% CI: 0.71; 3.61) in the study cohort as compared with the sex-, age- and calendar-time-specific national rates. These findings may in part reflect the relatively young age of study subjects (median attained age of 33.4 years), and long latency for some radiation-related solid cancers. Conclusions: We found no evidence of statistically significant increases in solid cancer, lymphoma and leukemia incidence 25 years after childhood exposure in the study cohort; however, it is important to continue follow-up non-thyroid cancers in individuals exposed to low-level radiation at radiosensitive ages. - Highlights: • We monitor cancers in a Belarusian cohort of exposed as children due to Chernobyl. • No increase in solid cancer rates was found as compared to the national rates. • An elevation of leukemia rates was detected, although statistically insignificant. • Results are consistent with those in a cohort of exposed as children in Ukraine. • Further monitoring of cancer situation in this cohort is warranted.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Exposure to perfluoroalkyl substances and associations with serum thyroid hormones in a remote population of Alaska Natives

Highlights: • Serum concentrations PFOA, PFNA, PFUnA and PFDA were positively associated with TSH in individual models. • No serum PFASs are associated with total or free T{sub 4}. • The associations between serum PFOA and PFNA and free T{sub 3,} as well as PFNA and total T3 are modified by sex. • The effect of PFAS exposure on thyroid hormone homeostasis differs between sexes. Perfluoroalkyl substances (PFASs) are known to accumulate in traditional food animals of the Arctic, and arctic indigenous peoples may be exposed via consumption of subsistence-harvested animals. PFASs are suspected of disrupting thyroid hormone homeostasis in humans. The aim of this study is to assess the relationship between serum PFASs and thyroid function in a remote population of Alaska Natives. Serum samples were collected from 85 individuals from St. Lawrence Island, Alaska. The concentrations of 13 PFASs, as well as free and total thyroxine (T{sub 4}), free and total triiodothyronine (T{sub 3}), and thyrotropin (TSH) were quantified in serum samples. The relationships between circulating concentrations of PFASs and thyroid hormones were assessed using multiple linear regression fit with generalized estimating equations. Several PFASs, including perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA), were positively associated with TSH concentrations when modeled individually. PFOS and PFNA were significantly associated with free T{sub 3} and PFNA was significantly associated with total T{sub 3} in models with PFAS*sex interactive terms; these associations suggested negative associations in men and positive associations in women. PFASs were not significantly associated with concentrations of free or total T{sub 4}. Serum PFASs are associated with circulating thyroid hormone concentrations in a remote population of Alaska Natives. The effects of PFAS exposure on thyroid hormone homeostasis may differ between sexes.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Intracellular redox status controls spherogenicity, an in vitro cancer stem cell marker, in thyroid cancer cell lines

Highlights: • Higher spherogenicity in ROS{sup low} fractions of thyroid cancer cell lines. • Flexibility of ROS levels. • Functional importance of ROS levels for cancer stemness. • Lower GSH levels and quiescent state for cellular oxidative phosphorylation/glycolysis in ROS{sup low} cells. Cancer stem cells (CSCs), a small fraction of a tumor mass, are proposed to be highly crucial for cancer initiation, recurrence and metastasis. We have recently found that aldehyde dehydrogenase (ALDH) 1A3 is a CSC marker in some thyroid cancer cell lines, whose functional activity is, however, not relevant for thyroid cancer stemness. Since previous studies on malignancies in other organs suggest that intracellular reactive oxygen species (ROS) might be a functional and targetable CSC marker, the present study was conducted to elucidate the significance of ROS as a functional CSC marker in thyroid cancer cell lines. We first found that ROS levels controlled spherogenicity; that is, ROS{sup low} cells were more spherogenic than ROS{sup high} cells. However, unlike typical CSCs in other cancers, CSC-like ROS{sup low} cells in thyroid cancer cells were plastic and were not accompanied by de-differentiation status (i.e., expression of stemness markers/thyroid-specific transcription factors) or chemo-/radio-resistance. The lower levels of ROS were functionally critical because a forced increase in ROS levels by L-buthionine-S,R-sulfoximine, an inhibitor of glutathione (GSH) synthesis, and irradiation suppressed spherogenicity. ROS levels were also correlated with the number of double strand DNA breaks determined by 53BP1 staining. Lower ROS levels appear to be a result of decreased mitochondrial oxidative phosphorylation and elevated GSH contents. Given the importance of CSC-targeted therapy for achieving long-term disease eradication by exhausting self-renewal and growth potential of cancer tissues, ROS may be a good candidate for CSC-targeted therapy in thyroid cancer.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1997

Interaction of thyroid state and denervation on skeletal myosin heavy chain expression

The goal of this study was to examine the effects of altered thyroid state and denervation (Den) on skeletal myosin heavy chain (MHC) expression in the plantaris and soleus muscles. Rats were subjected to unilateral denervation (Den) and randomly assigned to one of three groups: (1) euthyroid; (2) hyperthyroid; (3) and hypothyroid. Denervation caused severe muscle atrophy and muscle-type specific MHC transformation. Denervation transformed the soleus to a faster muscle, and its effects required the presence of circulating thyroid hormone. In contrast, denervation transformed the plantaris to a slower muscle independently of thyroid state. Furthermore, thyroid hormone effects did not depend upon innervation status in the soleus, while they required the presence of the nerve in the plantaris. Collectively, these findings suggest that both thyroid hormone and intact nerve (a) differentially affect MHC transformations in fast and slow muscle; and (b) are important factors in regulating the optimal expression of both type I and IIB MHC genes. This research suggests that for patients with nerve damage and/or paralysis, both muscle mass and biochemical properties can also be affected by the thyroid state.

NASA Discipline Musculoskeletal↗
DOE OSTI2018

LRP4 promotes proliferation, migration, and invasion in papillary thyroid cancer

Dysregulation of cell proliferation and death is considered the foundation of the malignant biological characteristics of cancer. In this study, we conducted a comprehensive analysis of a massively parallel whole transcriptome resequencing of paired papillary thyroid cancer and normal thyroid tissues from 19 patients. In addition, we found that LRP4, a member of the low-density lipoprotein receptor-related protein family, is significantly overexpressed in thyroid carcinoma. We demonstrated through quantitative real-time polymerase chain reaction (qRT-PCR) that LRP4 is upregulated in papillary thyroid cancer (PTC) tissues. This observation was also consistent with data analyzed from The Cancer Genome Atlas (TCGA) cohort. Thus, the biological role of LRP4 in the thyroid cancer in the present study was investigated using the PTC cell lines TPC1, BCPAP and KTC-1. In these cell lines, the mRNA level of LRP4 was higher than normal thyroid cancer cell named HTORI3. In vitro experiments demonstrated that LRP4 downregulation significantly inhibited the colony formation, proliferation, migration, and invasion of the three PTC cell lines. Knockdown of LRP4 by small interfering RNA (siRNA) in those cell lines decreased the protein expression of N-cadherin, Enhancer of zeste homolog 2 (EZH2), and Zinc finger E-box-binding home-box 1 (ZEB1). Furthermore, LRP4 knockdown significantly reduced the levels of phosphorylated PI3K in the PTC cell lines. In conclusion, the present study indicated that LRP4 is a gene associated with PTC and might become a potential therapeutic target.

60 APPLIED LIFE SCIENCES↗