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Edna Teruko Kimura - One of the best experts on this subject based on the ideXlab platform.
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Thyroid Follicular Cell loss of differentiation induced by microrna mir 17 92 cluster is attenuated by crispr cas9n gene silencing in anaplastic Thyroid cancer
Thyroid, 2020Co-Authors: Cesar Seigi Fuziwara, Kelly Cristina Saito, Edna Teruko KimuraAbstract:Background: Loss of the expression of Thyroid differentiation markers such as sodium iodide symporter (NIS) and, consequently, radioiodine refractoriness is observed in aggressive papillary Thyroid...
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Image_1_The Highly Expressed FAM83F Protein in Papillary Thyroid Cancer Exerts a Pro-Oncogenic Role in Thyroid Follicular Cells.TIF
2019Co-Authors: Cesar Seigi Fuziwara, Suzana Garcia Leoni, Kelly Cristina Saito, Ângela Flávia Logullo Waitzberg, Edna Teruko KimuraAbstract:Thyroid cancer is the most common endocrine cancer with predominant prevalence of papillary Thyroid cancer (PTC) histotype. MAPK signaling genetic alterations are frequent in PTC, affecting more than 80% of cases. These alterations constitutively activate MAPK signaling cross-regulating different pro-oncogenic pathways. However, additional molecular alterations associated with Thyroid cancer are not completely understood. In this extent, the new family of proteins named FAM83 (FAMily with sequence similarity 83) was recently identified as mediator of oncogenic signaling in different types of cancer. Here we report FAM83F as a novel highly expressed protein in PTC. We evaluated FAM83F levels in 106 PTC specimens, 34 goiter, and 41 adjacent non-tumoral human Thyroid, and observed FAM83F cytoplasmic overexpression in 71% of PTC (76 of 106) while goiter tissues showed nuclear positivity and normal Thyroid showed no staining by immunohistochemistry. Moreover, TSH-induced goiter and BRAFT1799A-induced PTC animal models also showed FAM83F activation. In vitro, we generated a stable Thyroid Cell line PCCL3 with FAM83F overexpression and observed that FAM83F deregulates Thyroid Follicular Cell biology leading to loss of Thyroid differentiation genes such as Sodium-Iodide Symporter (NIS), reactivation of stem Cell markers such as LIN28B and SOX2, induction of Cell migration and resistance to doxorubicin-induced apoptosis. Moreover, FAM83F activates MAPK signaling through interaction with BRAF and RAF while impairs TGFβ antiproliferative signaling transduction. In this study, we showed FAM83F as a new pro-oncogenic protein overexpressed in Thyroid cancer that modulates Thyroid Follicular Cell biology and differentiation through cross-regulation of MAPK and TGFβ signaling.
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Table_1_The Highly Expressed FAM83F Protein in Papillary Thyroid Cancer Exerts a Pro-Oncogenic Role in Thyroid Follicular Cells.DOC
2019Co-Authors: Cesar Seigi Fuziwara, Suzana Garcia Leoni, Kelly Cristina Saito, Ângela Flávia Logullo Waitzberg, Edna Teruko KimuraAbstract:Thyroid cancer is the most common endocrine cancer with predominant prevalence of papillary Thyroid cancer (PTC) histotype. MAPK signaling genetic alterations are frequent in PTC, affecting more than 80% of cases. These alterations constitutively activate MAPK signaling cross-regulating different pro-oncogenic pathways. However, additional molecular alterations associated with Thyroid cancer are not completely understood. In this extent, the new family of proteins named FAM83 (FAMily with sequence similarity 83) was recently identified as mediator of oncogenic signaling in different types of cancer. Here we report FAM83F as a novel highly expressed protein in PTC. We evaluated FAM83F levels in 106 PTC specimens, 34 goiter, and 41 adjacent non-tumoral human Thyroid, and observed FAM83F cytoplasmic overexpression in 71% of PTC (76 of 106) while goiter tissues showed nuclear positivity and normal Thyroid showed no staining by immunohistochemistry. Moreover, TSH-induced goiter and BRAFT1799A-induced PTC animal models also showed FAM83F activation. In vitro, we generated a stable Thyroid Cell line PCCL3 with FAM83F overexpression and observed that FAM83F deregulates Thyroid Follicular Cell biology leading to loss of Thyroid differentiation genes such as Sodium-Iodide Symporter (NIS), reactivation of stem Cell markers such as LIN28B and SOX2, induction of Cell migration and resistance to doxorubicin-induced apoptosis. Moreover, FAM83F activates MAPK signaling through interaction with BRAF and RAF while impairs TGFβ antiproliferative signaling transduction. In this study, we showed FAM83F as a new pro-oncogenic protein overexpressed in Thyroid cancer that modulates Thyroid Follicular Cell biology and differentiation through cross-regulation of MAPK and TGFβ signaling.
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The Highly Expressed FAM83F Protein in Papillary Thyroid Cancer Exerts a Pro-Oncogenic Role in Thyroid Follicular Cells
Frontiers Media S.A., 2019Co-Authors: Cesar Seigi Fuziwara, Suzana Garcia Leoni, Kelly Cristina Saito, Ângela Flávia Logullo Waitzberg, Edna Teruko KimuraAbstract:Thyroid cancer is the most common endocrine cancer with predominant prevalence of papillary Thyroid cancer (PTC) histotype. MAPK signaling genetic alterations are frequent in PTC, affecting more than 80% of cases. These alterations constitutively activate MAPK signaling cross-regulating different pro-oncogenic pathways. However, additional molecular alterations associated with Thyroid cancer are not completely understood. In this extent, the new family of proteins named FAM83 (FAMily with sequence similarity 83) was recently identified as mediator of oncogenic signaling in different types of cancer. Here we report FAM83F as a novel highly expressed protein in PTC. We evaluated FAM83F levels in 106 PTC specimens, 34 goiter, and 41 adjacent non-tumoral human Thyroid, and observed FAM83F cytoplasmic overexpression in 71% of PTC (76 of 106) while goiter tissues showed nuclear positivity and normal Thyroid showed no staining by immunohistochemistry. Moreover, TSH-induced goiter and BRAFT1799A-induced PTC animal models also showed FAM83F activation. In vitro, we generated a stable Thyroid Cell line PCCL3 with FAM83F overexpression and observed that FAM83F deregulates Thyroid Follicular Cell biology leading to loss of Thyroid differentiation genes such as Sodium-Iodide Symporter (NIS), reactivation of stem Cell markers such as LIN28B and SOX2, induction of Cell migration and resistance to doxorubicin-induced apoptosis. Moreover, FAM83F activates MAPK signaling through interaction with BRAF and RAF while impairs TGFβ antiproliferative signaling transduction. In this study, we showed FAM83F as a new pro-oncogenic protein overexpressed in Thyroid cancer that modulates Thyroid Follicular Cell biology and differentiation through cross-regulation of MAPK and TGFβ signaling
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high iodine blocks a notch mir 19 loop activated by the brafv600e oncoprotein and restores the response to tgfβ in Thyroid Follicular Cells
Thyroid, 2014Co-Authors: Cesar Seigi Fuziwara, Edna Teruko KimuraAbstract:Background: Excess iodine inhibits Thyroid Follicular Cell proliferation associated with TGFβ pathway activation, although Thyroid cancers are frequently refractory to TGFβ signaling. The TGFβ pathway is predicted to be regulated by miR-17-92 cluster microRNAs. MicroRNAs are small noncoding RNAs that inhibit target mRNA translation and have emerged as potent modulators of tumorigenesis. Although the BRAFV600E mutation is the most prevalent alteration in Thyroid cancer, the impact of iodine intake on BRAF-mediated oncogenesis remains unclear. Therefore, the aim of this study was to investigate the influence of high iodine on miR-17-92 transcriptional regulation and expression in Thyroid Cells expressing activated BRAF. Methods: Rat Thyroid Follicular Cells that conditionally express BRAFV600E under doxycycline stimulation (PC-BRAFV600E-6) were derived from the PCCl3 line. These Cells were treated with doxycycline for two days, in the absence or presence of 10 μM sodium iodide. The Thyroid cancer Cell lines...
Masao Hirose - One of the best experts on this subject based on the ideXlab platform.
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involvement of pten akt signaling in capsular invasive carcinomas developed in a rat two stage Thyroid carcinogenesis model after promotion with sulfadimethoxine
Journal of Cancer Research and Clinical Oncology, 2011Co-Authors: Sayaka Kemmochi, Hitoshi Fujimoto, Miwa Takahashi, Kunitoshi Mitsumori, Akiyoshi Nishikawa, Masao Hirose, Kaoru Inoue, Makoto ShibutaniAbstract:Purpose Rat Thyroid Follicular Cell carcinomas invading into the Thyroid capsule are highly produced by promotion with sulfadimethoxine (SDM) in a rat two-stage Thyroid carcinogenesis model. In this study, we investigated the participation of phosphoinositide 3-kinase (PI3K) signaling pathway that is associated with malignant phenotypes of many cancers on the development of SDM-induced capsular invasive carcinomas.
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developmental toxicity of brominated flame retardants tetrabromobisphenol a and 1 2 5 6 9 10 hexabromocyclododecane in rat offspring after maternal exposure from mid gestation through lactation
Reproductive Toxicology, 2009Co-Authors: Yukie Saegusa, Hitoshi Fujimoto, Miwa Takahashi, Kunitoshi Mitsumori, Akiyoshi Nishikawa, Masao Hirose, Kaoru Inoue, Gyehyeong Woo, Makoto ShibutaniAbstract:Abstract To evaluate developmental exposure effects of two brominated flame retardants, tetrabromobisphenol A (TBBPA) and 1,2,5,6,9,10-hexabromocyclododecane (HBCD), pregnant Sprague–Dawley rats were administered either chemical at doses of 100, 1000 or 10,000 ppm in a soy-free diet from gestation day 10 until the day 20 after delivery. Offspring exposed to TBBPA showed dose-unrelated slight decreases of serum triiodothyronine (T3) concentration at postnatal day 20, and there was no evidence of hypoThyroidism-related neuronal mismigration and impaired oligodendroglial development as judged by morphometric analyses of NeuN-immunoreactive neuronal distribution in the hippocampal CA1, and area of corpus callosum as well as density of 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase)-immunoreactive oligodendrocytes in the cingulate deep cortex at the adult stage. On the other hand, HBCD exerted a weak hypoThyroidism evident with increases in Thyroid weight, Thyroid Follicular Cell hypertrophy and serum concentrations of Thyroid-stimulating hormone as well as decreases of serum T3 concentrations in offspring at 10,000 ppm at weaning. Increased Thyroid weights and decreased serum T3 concentrations were also observed in the adult stage from 1000 ppm. With regard to the effect on brain development, HBCD reduced density of CNPase-positive oligodendrocytes at 10,000 ppm, suggesting an impaired oligodendroglial development. Results thus suggest that TBBPA did not exert developmental brain effects, while HBCD did, and 100 ppm was determined to be the no-observed-adverse-effect level of HBCD from changes in Thyroid parameters at the adult stage by maternal exposure, translating into 8.1–21.3 mg/kg-d.
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assessment of developmental effects of hypoThyroidism in rats from in utero and lactation exposure to anti Thyroid agents
Reproductive Toxicology, 2009Co-Authors: Makoto Shibutani, Hitoshi Fujimoto, Miwa Takahashi, Masao Hirose, Kaoru Inoue, Gyehyeong Woo, Yukie Saegusa, Akiyoshi NishikawaAbstract:To clarify the developmental effects of hypoThyroidism and to establish a detection system of resultant brain retardation, pregnant rats were administered 3 or 12 ppm of 6-propyl-2-thiouracil (PTU) or 200 ppm of methimazole (MMI) in the drinking water from gestation day 10 to postnatal day 20 and maintained after weaning until 11 weeks of age (adult stage). Offspring displayed evidence of growth retardation lasting into the adult stage, which was particularly prominent in males. Except for hypoThyroidism-related Thyroid Follicular Cell hypertrophy, most histopathological changes that appeared at the end of chemical exposure were related to growth retardation and reversed by the adult stage. A delayed onset of puberty and an adult stage gonadal enlargement occurred by exposure to anti-Thyroid agents, both being especially evident in males, and this effect might be related to gonadal growth suppression during exposure. At the adult stage, the distribution variability of hippocampal CA1 pyramidal neurons reflecting mismigration could be detected in animals receiving both thyrotoxins, with a dose-dependent effect by PTU. Similarly, a reduction in the area of the corpus callosum and oligodendroglial Cell numbers in the cerebral deep cortex, both reflecting impaired oligodendroglial development, were detected in rats administered both chemicals. Thus, all effects, except for impaired brain development, might be linked to systemic growth retardation, and the brain morphometric methods employed in this study may be useful to evaluate the potency of chemicals to induce hypoThyroidism-related brain retardation.
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depression of t Cell mediated immunity reduces sulfadimethoxine induced capsular inflammation and inhibits associated development of invasive Thyroid Follicular Cell carcinomas in rats
Cancer Science, 2007Co-Authors: Toshio Imai, Junichi Onose, Mai Hasumura, Masao HiroseAbstract:We previously demonstrated that Thyroid capsular inflammation induced by continuous treatment with the antiThyroidal agent sulfadimethoxine is associated with development of invasive Follicular Cell carcinomas in rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). The inflammatory changes are characterized by large numbers of macrophages and lymphocytes as well as fibroblasts and we hypothesized that it might be enhanced by interplay between macrophages and T Cells. To clarify this hypothesis, a comparative study was conducted between athymic nude (rnu/rnu) rats and euthymic (rnu/+) littermates initiated with DHPN (2800 mg/kg, s.c.) followed by sulfadimethoxine treatment in drinking water (0.1%) for 10 weeks. In rnu/+rats, marked capsular thickening with inflammation was induced along with invasive Follicular Cell carcinomas (2.8 ± 1.3/rat). In rnu/rnu rats, limited fibrous capsular thickening was noted with or without minimal inflammatory change, and the multiplicity of invasive carcinomas was significantly lower (1.1 ± 1.0/rat, P < 0.01). Inducible nitric oxide synthase expression in the inflamed lesions was detected in three of 10 rnu/+rats but in none of the rnu/rnu animals. The results thus suggest that development of invasive carcinomas is enhanced by capsular inflammation mediated by T Cells, and inducible nitric oxide synthase induction may play a role in tumor progression. (Cancer Sci 2007; 98: 294–298)
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indomethacin induces small intestinal damage and inhibits amitrole associated Thyroid carcinogenesis in rats initiated with n bis 2 hydroxypropyl nitrosamine
Toxicology Letters, 2006Co-Authors: Toshio Imai, Junichi Onose, Mai Hasumura, Tamotsu Takizawa, Masao HiroseAbstract:Effects of intestinal damage on Thyroid carcinogenesis due to amitrole (AT) were examined in F344 male rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). In experiment 1, rats were provided with diet containing 0.03% AT for 20 weeks after a single subcutaneous injection of DHPN (2800 mg/kg body weight), and concomitantly received 0.01% indomethacin (IM) in the diet to cause small intestinal damage or 1% dextran sodium sulfate (DSS) in the drinking water for induction of colitis following a schedule of intermittent 1-week administration and 1-week withdrawal for a total of 10 times. Groups without AT- and/or IM or DSS treatment were also included. Histopathological examination revealed significant reduction in the incidence and multiplicity of Follicular Cell adenomas and adenocarcinomas in the group concomitantly treated with IM, but no change in the DSS group, as compared with the AT alone group. In experiment 2, rats were similarly fed diet containing AT for 3 weeks with concomitant IM or DSS treatment after a DHPN initiation, and serum Thyroid stimulating hormone levels were found to be significantly elevated only in the IM case. The increase in Thyroid Follicular Cell proliferation due to AT was also clearly suppressed in the group concomitantly treated with IM. From these findings, IM-induced intestinal damage may inhibit Thyroid carcinogeneisis in rats, although contributions of other factors, such as a direct inhibitory effect of IM to Thyroid Follicular Cell proliferation cannot be ruled out.
Cesar Seigi Fuziwara - One of the best experts on this subject based on the ideXlab platform.
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Thyroid Follicular Cell loss of differentiation induced by microrna mir 17 92 cluster is attenuated by crispr cas9n gene silencing in anaplastic Thyroid cancer
Thyroid, 2020Co-Authors: Cesar Seigi Fuziwara, Kelly Cristina Saito, Edna Teruko KimuraAbstract:Background: Loss of the expression of Thyroid differentiation markers such as sodium iodide symporter (NIS) and, consequently, radioiodine refractoriness is observed in aggressive papillary Thyroid...
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Image_1_The Highly Expressed FAM83F Protein in Papillary Thyroid Cancer Exerts a Pro-Oncogenic Role in Thyroid Follicular Cells.TIF
2019Co-Authors: Cesar Seigi Fuziwara, Suzana Garcia Leoni, Kelly Cristina Saito, Ângela Flávia Logullo Waitzberg, Edna Teruko KimuraAbstract:Thyroid cancer is the most common endocrine cancer with predominant prevalence of papillary Thyroid cancer (PTC) histotype. MAPK signaling genetic alterations are frequent in PTC, affecting more than 80% of cases. These alterations constitutively activate MAPK signaling cross-regulating different pro-oncogenic pathways. However, additional molecular alterations associated with Thyroid cancer are not completely understood. In this extent, the new family of proteins named FAM83 (FAMily with sequence similarity 83) was recently identified as mediator of oncogenic signaling in different types of cancer. Here we report FAM83F as a novel highly expressed protein in PTC. We evaluated FAM83F levels in 106 PTC specimens, 34 goiter, and 41 adjacent non-tumoral human Thyroid, and observed FAM83F cytoplasmic overexpression in 71% of PTC (76 of 106) while goiter tissues showed nuclear positivity and normal Thyroid showed no staining by immunohistochemistry. Moreover, TSH-induced goiter and BRAFT1799A-induced PTC animal models also showed FAM83F activation. In vitro, we generated a stable Thyroid Cell line PCCL3 with FAM83F overexpression and observed that FAM83F deregulates Thyroid Follicular Cell biology leading to loss of Thyroid differentiation genes such as Sodium-Iodide Symporter (NIS), reactivation of stem Cell markers such as LIN28B and SOX2, induction of Cell migration and resistance to doxorubicin-induced apoptosis. Moreover, FAM83F activates MAPK signaling through interaction with BRAF and RAF while impairs TGFβ antiproliferative signaling transduction. In this study, we showed FAM83F as a new pro-oncogenic protein overexpressed in Thyroid cancer that modulates Thyroid Follicular Cell biology and differentiation through cross-regulation of MAPK and TGFβ signaling.
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Table_1_The Highly Expressed FAM83F Protein in Papillary Thyroid Cancer Exerts a Pro-Oncogenic Role in Thyroid Follicular Cells.DOC
2019Co-Authors: Cesar Seigi Fuziwara, Suzana Garcia Leoni, Kelly Cristina Saito, Ângela Flávia Logullo Waitzberg, Edna Teruko KimuraAbstract:Thyroid cancer is the most common endocrine cancer with predominant prevalence of papillary Thyroid cancer (PTC) histotype. MAPK signaling genetic alterations are frequent in PTC, affecting more than 80% of cases. These alterations constitutively activate MAPK signaling cross-regulating different pro-oncogenic pathways. However, additional molecular alterations associated with Thyroid cancer are not completely understood. In this extent, the new family of proteins named FAM83 (FAMily with sequence similarity 83) was recently identified as mediator of oncogenic signaling in different types of cancer. Here we report FAM83F as a novel highly expressed protein in PTC. We evaluated FAM83F levels in 106 PTC specimens, 34 goiter, and 41 adjacent non-tumoral human Thyroid, and observed FAM83F cytoplasmic overexpression in 71% of PTC (76 of 106) while goiter tissues showed nuclear positivity and normal Thyroid showed no staining by immunohistochemistry. Moreover, TSH-induced goiter and BRAFT1799A-induced PTC animal models also showed FAM83F activation. In vitro, we generated a stable Thyroid Cell line PCCL3 with FAM83F overexpression and observed that FAM83F deregulates Thyroid Follicular Cell biology leading to loss of Thyroid differentiation genes such as Sodium-Iodide Symporter (NIS), reactivation of stem Cell markers such as LIN28B and SOX2, induction of Cell migration and resistance to doxorubicin-induced apoptosis. Moreover, FAM83F activates MAPK signaling through interaction with BRAF and RAF while impairs TGFβ antiproliferative signaling transduction. In this study, we showed FAM83F as a new pro-oncogenic protein overexpressed in Thyroid cancer that modulates Thyroid Follicular Cell biology and differentiation through cross-regulation of MAPK and TGFβ signaling.
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The Highly Expressed FAM83F Protein in Papillary Thyroid Cancer Exerts a Pro-Oncogenic Role in Thyroid Follicular Cells
Frontiers Media S.A., 2019Co-Authors: Cesar Seigi Fuziwara, Suzana Garcia Leoni, Kelly Cristina Saito, Ângela Flávia Logullo Waitzberg, Edna Teruko KimuraAbstract:Thyroid cancer is the most common endocrine cancer with predominant prevalence of papillary Thyroid cancer (PTC) histotype. MAPK signaling genetic alterations are frequent in PTC, affecting more than 80% of cases. These alterations constitutively activate MAPK signaling cross-regulating different pro-oncogenic pathways. However, additional molecular alterations associated with Thyroid cancer are not completely understood. In this extent, the new family of proteins named FAM83 (FAMily with sequence similarity 83) was recently identified as mediator of oncogenic signaling in different types of cancer. Here we report FAM83F as a novel highly expressed protein in PTC. We evaluated FAM83F levels in 106 PTC specimens, 34 goiter, and 41 adjacent non-tumoral human Thyroid, and observed FAM83F cytoplasmic overexpression in 71% of PTC (76 of 106) while goiter tissues showed nuclear positivity and normal Thyroid showed no staining by immunohistochemistry. Moreover, TSH-induced goiter and BRAFT1799A-induced PTC animal models also showed FAM83F activation. In vitro, we generated a stable Thyroid Cell line PCCL3 with FAM83F overexpression and observed that FAM83F deregulates Thyroid Follicular Cell biology leading to loss of Thyroid differentiation genes such as Sodium-Iodide Symporter (NIS), reactivation of stem Cell markers such as LIN28B and SOX2, induction of Cell migration and resistance to doxorubicin-induced apoptosis. Moreover, FAM83F activates MAPK signaling through interaction with BRAF and RAF while impairs TGFβ antiproliferative signaling transduction. In this study, we showed FAM83F as a new pro-oncogenic protein overexpressed in Thyroid cancer that modulates Thyroid Follicular Cell biology and differentiation through cross-regulation of MAPK and TGFβ signaling
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high iodine blocks a notch mir 19 loop activated by the brafv600e oncoprotein and restores the response to tgfβ in Thyroid Follicular Cells
Thyroid, 2014Co-Authors: Cesar Seigi Fuziwara, Edna Teruko KimuraAbstract:Background: Excess iodine inhibits Thyroid Follicular Cell proliferation associated with TGFβ pathway activation, although Thyroid cancers are frequently refractory to TGFβ signaling. The TGFβ pathway is predicted to be regulated by miR-17-92 cluster microRNAs. MicroRNAs are small noncoding RNAs that inhibit target mRNA translation and have emerged as potent modulators of tumorigenesis. Although the BRAFV600E mutation is the most prevalent alteration in Thyroid cancer, the impact of iodine intake on BRAF-mediated oncogenesis remains unclear. Therefore, the aim of this study was to investigate the influence of high iodine on miR-17-92 transcriptional regulation and expression in Thyroid Cells expressing activated BRAF. Methods: Rat Thyroid Follicular Cells that conditionally express BRAFV600E under doxycycline stimulation (PC-BRAFV600E-6) were derived from the PCCl3 line. These Cells were treated with doxycycline for two days, in the absence or presence of 10 μM sodium iodide. The Thyroid cancer Cell lines...
Curtis D. Klaassen - One of the best experts on this subject based on the ideXlab platform.
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Thyroid Cancer in Humans
2016Co-Authors: Curtis D. Klaassen, M. HoodAbstract:The effects of microsomal enzyme inducers on Thyroid hormone homeostasis and the Thyroid gland are of concern. We have investigated the effects of microsomal enzyme inducers on Thyroid Follicular Cell proliferation and Thyroid hormone metabolism in rats. We have shown that small increases in serum TSH can result in large increases in Thyroid Follicular Cell proliferation. Furthermore, only those microsomal enzyme inducers that increase serum TSH—that is, phenobarbi tal (PB) and pregnenolone-16-carbonitrile (PCN)—increase Thyroid Follicular Cell proliferation, whereas those microsomal enzyme inducers that do not increase serum TSH— that is, 3-methylcholanthrene (3MC) and Aroclor 1254 (PCB)—do not increase Thyroid Follicular Cell proliferation. Deiodination does not appear to be the reason why serum T3 concentrations are maintained in microsomal enzyme inducer–treated rats. We have also shown that those microsomal enzyme inducers that increase serum TSH increase T3 UDP-glucuronosyltransferase (UGT) activity, whereas those microsomal enzyme inducers that do not increase serum TSH do not increase T3 UGT activity. This nding suggests that induction of T3 glucuronidation, rather than T4 glucuronidation, mediates increases in serum TSH of microsomal enzyme inducer treated rats
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inhibition of gap junctional interCellular communication in Thyroid Follicular Cells by propylthiouracil and low iodine diet
Toxicology, 2000Co-Authors: Kyle L. Kolaja, Jay S. Petrick, Curtis D. KlaassenAbstract:Propylthiouracil (PTU) or low-iodine diet (LID) treatment increases Thyroid-Follicular-Cell proliferation, possibly by disrupting the movement of small molecules (<1.2 kD) through membrane channels called gap junctions. Numerous tumor promoters and proliferative disease states exhibit inhibited gap-junctional-interCellular communication (GJIC) prior to the induction of Cell proliferation, yet the association between GJIC and apoptosis is unclear. In the present study, we used an ex vivo method to examine whether GJIC is inhibited in the Thyroid of PTU- or LID-treated rats. In addition, the effect of these models of hypoThyroidism on Thyroid-Follicular-Cell proliferation and apoptosis was examined to determine the association between GJIC and Cell homeostasis. After 14 days of treatment of either PTU or LID (plus 1% KClO4 in the drinking water), serum tri-iodothyronine (T3) and thyroxine, (T4) was decreased to nearly undetectable levels and serum TSH was increased in PTU- and LID-treated rats. At the same time point, GJIC was decreased 30–35% in PTU- and LID-treated rats while Thyroid-Follicular-Cell proliferation increased nearly threefold in both treatment groups. Interestingly, apoptosis increased twofold in both hypoThyroid treatment groups. These data suggest that PTU or LID treatment inhibit Thyroid GJIC during a state of increased Thyroid-Follicular-Cell proliferation and apoptosis. While the increase in proliferation was anticipated, the paradoxical increase in apoptosis during decreased GJIC in Thyroid-Follicular Cells warrants further examination.
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effects of microsomal enzyme inducers on Thyroid Follicular Cell proliferation hyperplasia and hypertrophy
Toxicology and Applied Pharmacology, 1999Co-Authors: Alan Hood, Raj Hashmi, Curtis D. KlaassenAbstract:Abstract The microsomal enzyme inducer (MEI), phenobarbital (PB), has been proposed to promote Thyroid tumors by increasing the biotransformation and elimination of T 4 , resulting in an increase in serum Thyroid-stimulating hormone (TSH). In turn, TSH stimulates Thyroid gland function, growth, and ultimately neoplasia. The dose-dependent effects of MEI on Thyroid-Follicular Cell proliferation, a measure of Thyroid gland growth, has not been reported. In the present study, it was hypothesized that MEIs that increase TSH would stimulate Thyroid-Follicular Cell proliferation and the total number of Thyroid-Follicular Cells. Male Sprague–Dawley rats were fed either a basal diet or a diet containing PB (at 300, 600, 1200, or 2400 ppm), pregnenolone-16α-carbonitrile (PCN) (at 200, 400, 800, or 1600 ppm), 3-methylcholanthrene (3MC) (at 50, 100, 200, or 400 ppm), or Aroclor 1254 (PCB) (at 25, 50, 100, or 200 ppm) for 7 days. PB and PCN increased TSH 65% and 95%, respectively, whereas 3MC and PCB did not appreciably affect TSH. PB and PCN increased Thyroid-Follicular Cell proliferation 625% and 1200%, respectively, whereas 3MC and PCB did not have a consistent or appreciable effect. The total number of Thyroid-Follicular Cells was not significantly increased by MEI treatment. In conclusion, small increases in TSH by PB and PCN produced large increases in Thyroid-Follicular Cell proliferation, which did not result in a comparable increase in the total number of Thyroid-Follicular Cells. Furthermore, MEI that did not increase TSH did not consistently or appreciably increase Thyroid-Follicular Cell proliferation or Cell number.
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sensitivity of Thyroid gland growth to Thyroid stimulating hormone tsh in rats treated with antiThyroid drugs
Toxicological Sciences, 1999Co-Authors: Alan M Hood, Ya Ping Liu, Vincent H Gattone, Curtis D. KlaassenAbstract:AntiThyroid drugs and phenobarbital (PB) have been shown to promote Thyroid tumors in rats. It has been proposed that increased Thyroid-stimulating hormone (TSH) mediates the Thyroid tumor-promoting effect of antiThyroid drugs and PB, and is increased because of decreased thyroxine (T4) concentration. However, PB is much less effective than antiThyroid drugs at increasing TSH. It has been proposed that small increases in serum TSH produced by PB treatment is sufficient to promote Thyroid tumors. However, the level to which TSH must be increased to stimulate the Thyroid gland has not been reported. Therefore, we have examined the effect of increasing serum TSH concentration on Thyroid growth by measuring Thyroid gland weight and Thyroid Follicular Cell proliferation. Serum TSH concentrations were increased by feeding rats various concentrations of propylthiouracil (PTU) or methimazole (MMI) for 21 days. Serum total T4, free T4, total T3 (triiodothyronine), free T3, and TSH concentrations were measured by radioimmunoassay. Thyroid Follicular Cell proliferation was measured by autoradiography and expressed as a labeling index (LI). PTU and MMI treatments reduced total and free T4 more than 95% by day 21, whereas total and free T3 were reduced 60%. TSH, Thyroid Follicular Cell proliferation and Thyroid weight were increased 560%, 1400%, and 200%, respectively, by day 21. TSH was significantly correlated with Thyroid weight and LI. Moderate increases in serum TSH of between 10 and 20 ng/ml increased the number of proliferating Thyroid Follicular Cells, but had no effect on Thyroid weight. These results support that small increases in serum TSH can be sufficient to stimulate Thyroid Follicular Cell proliferation. Furthermore, Thyroid Follicular Cell proliferation may be more useful than Thyroid weight alone for assessing alterations in Thyroid growth in rats treated with chemicals that produce only small to moderate increases in serum TSH.
Toshio Imai - One of the best experts on this subject based on the ideXlab platform.
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depression of t Cell mediated immunity reduces sulfadimethoxine induced capsular inflammation and inhibits associated development of invasive Thyroid Follicular Cell carcinomas in rats
Cancer Science, 2007Co-Authors: Toshio Imai, Junichi Onose, Mai Hasumura, Masao HiroseAbstract:We previously demonstrated that Thyroid capsular inflammation induced by continuous treatment with the antiThyroidal agent sulfadimethoxine is associated with development of invasive Follicular Cell carcinomas in rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). The inflammatory changes are characterized by large numbers of macrophages and lymphocytes as well as fibroblasts and we hypothesized that it might be enhanced by interplay between macrophages and T Cells. To clarify this hypothesis, a comparative study was conducted between athymic nude (rnu/rnu) rats and euthymic (rnu/+) littermates initiated with DHPN (2800 mg/kg, s.c.) followed by sulfadimethoxine treatment in drinking water (0.1%) for 10 weeks. In rnu/+rats, marked capsular thickening with inflammation was induced along with invasive Follicular Cell carcinomas (2.8 ± 1.3/rat). In rnu/rnu rats, limited fibrous capsular thickening was noted with or without minimal inflammatory change, and the multiplicity of invasive carcinomas was significantly lower (1.1 ± 1.0/rat, P < 0.01). Inducible nitric oxide synthase expression in the inflamed lesions was detected in three of 10 rnu/+rats but in none of the rnu/rnu animals. The results thus suggest that development of invasive carcinomas is enhanced by capsular inflammation mediated by T Cells, and inducible nitric oxide synthase induction may play a role in tumor progression. (Cancer Sci 2007; 98: 294–298)
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indomethacin induces small intestinal damage and inhibits amitrole associated Thyroid carcinogenesis in rats initiated with n bis 2 hydroxypropyl nitrosamine
Toxicology Letters, 2006Co-Authors: Toshio Imai, Junichi Onose, Mai Hasumura, Tamotsu Takizawa, Masao HiroseAbstract:Effects of intestinal damage on Thyroid carcinogenesis due to amitrole (AT) were examined in F344 male rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). In experiment 1, rats were provided with diet containing 0.03% AT for 20 weeks after a single subcutaneous injection of DHPN (2800 mg/kg body weight), and concomitantly received 0.01% indomethacin (IM) in the diet to cause small intestinal damage or 1% dextran sodium sulfate (DSS) in the drinking water for induction of colitis following a schedule of intermittent 1-week administration and 1-week withdrawal for a total of 10 times. Groups without AT- and/or IM or DSS treatment were also included. Histopathological examination revealed significant reduction in the incidence and multiplicity of Follicular Cell adenomas and adenocarcinomas in the group concomitantly treated with IM, but no change in the DSS group, as compared with the AT alone group. In experiment 2, rats were similarly fed diet containing AT for 3 weeks with concomitant IM or DSS treatment after a DHPN initiation, and serum Thyroid stimulating hormone levels were found to be significantly elevated only in the IM case. The increase in Thyroid Follicular Cell proliferation due to AT was also clearly suppressed in the group concomitantly treated with IM. From these findings, IM-induced intestinal damage may inhibit Thyroid carcinogeneisis in rats, although contributions of other factors, such as a direct inhibitory effect of IM to Thyroid Follicular Cell proliferation cannot be ruled out.
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sequential analysis of development of invasive Thyroid Follicular Cell carcinomas in inflamed capsular regions of rats treated with sulfadimethoxine after n bis 2 hydroxypropyl nitrosamine initiation
Toxicologic Pathology, 2004Co-Authors: Toshio Imai, Junichi Onose, Mai Hasumura, Makoto Ueda, Tamotsu Takizawa, Masao HiroseAbstract:A 2-stage Thyroid Follicular carcinogenesis model in rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN) is widely used to detect modifying effects of chemicals on Thyroid carcinogenesis. A number of goitrogens are known to strongly promote carcinogenesis, and the carcinomas often originate adjacent to the Thyroid capsule and show invasive growth into the capsule or adjacent tissues. To clarify mechanisms of progression to invasive carcinomas, we sequentially evaluated histopathological and immunohistochemical characteristics of Thyroids in male F344 rats treated with sulfadimethoxine (SDM, 0.1% in drinking water) for 0‐10 weeks beginning 1 week after DHPN initiation (2800 mg/kg body weight, single s.c. injection). In DHPN-SDM-treated rats, multiple focal hyperplasias and adenomas developed in Thyroid Follicular parenchyma at weeks 4 to 6. Apart from the proliferative lesions, capsular thickening with inflammatory Cell infiltration, mainly consisting of macrophages, and migration of Follicular epithelium into the capsule were also observed. Focal hyperplasias/adenomas adjacent to the capsule progressively developed to invasive carcinomas at weeks 6 to 10. In Thyroid parenchyma, malignant lesions were seldom observed. With SDM-treatment alone, although no neoplastic lesions were observed, capsular thickening with inflammation and epithelial migration resulted in intracapsular residual follicles. Intracapsular residual Follicular Cells as well as invasive and intraThyroidal carcinoma Cells generally showed increased Cell proliferative activity, coincidental with cytoplasmic/nuclear positivity for β-catenin. These results suggested that β-catenin activation related to capsular inflammation may play a role in development of invasive carcinomas but is insufficient for tumor formation by itself. Whether this is associated with mutations in the β-catenin gene remains to be clarified.