scholarly journals Growth Activation Alone Is Not Sufficient to Cause Metastatic Thyroid Cancer in a Mouse Model of Follicular Thyroid Carcinoma

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1929-1939 ◽  
Author(s):  
Changxue Lu ◽  
Li Zhao ◽  
Hao Ying ◽  
Mark C. Willingham ◽  
Sheue-yann Cheng
Keyword(s):  
Thyroid Hormone ◽  
Mouse Model ◽  
Thyroid Carcinoma ◽  
Focal Adhesion ◽  
Follicular Thyroid Carcinoma ◽  
Gene Knockout ◽  
Metastatic Cancer ◽  
Genetic Alterations ◽  
Human Thyroid ◽  
Migration And Invasion

TSH is the major stimulator of thyrocyte proliferation, but its role in thyroid carcinogenesis remains unclear. To address this question, we used a mouse model of follicular thyroid carcinoma (FTC) (TRβPV/PV mice). These mice, harboring a dominantly negative mutation (PV) of the thyroid hormone-β receptor (TRβ), exhibit increased serum thyroid hormone and elevated TSH. To eliminate TSH growth-stimulating effect, TRβPV/PV mice were crossed with TSH receptor gene knockout (TSHR−/−) mice. Wild-type siblings of TRβPV/PV mice were treated with an antithyroid agent, propylthiouracil, to elevate serum TSH for evaluating long-term TSH effect (WT-PTU mice). Thyroids from TRβPV/PVTSHR−/− showed impaired growth with no occurrence of FTC. Both WT-PTU and TRβPV/PV mice displayed enlarged thyroids, but only TRβPV/PV mice developed metastatic FTC. Molecular analyses indicate that PV acted, via multiple mechanisms, to activate the integrins-Src-focal adhesion kinase-p38 MAPK pathway and affect cytoskeletal restructuring to increase tumor cell migration and invasion. Thus, growth stimulated by TSH is a prerequisite but not sufficient for metastatic cancer to occur. Additional genetic alterations (such as PV), destined to alter focal adhesion and migration capacities, are required to empower hyperplastic follicular cells to invade and metastasize. These in vivo findings provide new insights in understanding carcinogenesis of the human thyroid.

scholarly journals Role of TSH in the Spontaneous Development of Asymmetrical Thyroid Carcinoma in Mice with a Targeted Mutation in a Single Allele of the Thyroid Hormone-β Receptor

Endocrinology ◽  
2012 ◽  
Vol 153 (10) ◽  
pp. 5090-5100 ◽  
Author(s):  
Li Zhao ◽  
Xuguang Zhu ◽  
Jeong Won Park ◽  
Laura Fozzatti ◽  
Mark Willingham ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Mouse Model ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Thyroid Tumor ◽  
Human Thyroid ◽  
Migration And Invasion ◽  
Wild Type ◽  
Single Allele

Abstract Mutations of the thyroid hormone receptor-β gene (THRB) cause resistance to thyroid hormone (RTH). A mouse model of RTH harboring a homozygous thyroid hormone receptor (TR)-β mutation known as PV (ThrbPV/PV mouse) spontaneously develops follicular thyroid cancer (FTC). Similar to RTH patients with mutations of two alleles of the THRB gene, the ThrbPV/PV mouse exhibits elevated thyroid hormones accompanied by highly nonsuppressible TSH. However, the heterozygous ThrbPV/+ mouse with mildly elevated TSH (∼2-fold) does not develop FTC. The present study examined whether the mutation of a single allele of the Thrb gene is sufficient to induce FTC in ThrbPV/+ mice under stimulation by high TSH. ThrbPV/+ mice and wild-type siblings were treated with propylthiouracil (PTU) to elevate serum TSH. ThrbPV/+mice treated with PTU (ThrbPV/+-PTU) spontaneously developed FTC similar to human thyroid cancer, but wild-type siblings treated with PTU did not. Interestingly, approximately 33% of ThrbPV/+-PTU mice developed asymmetrical thyroid tumors, as is frequently observed in human thyroid cancer. Molecular analyses showed activation of the cyclin 1-cyclin-dependent kinase-4-transcription factor E2F1 pathway to increase thyroid tumor cell proliferation of ThrbPV/+-PTU mice. Moreover, via extranuclear signaling, the PV also activated the integrin-Src-focal adhesion kinase-AKT-metalloproteinase pathway to increase migration and invasion of tumor cells. Therefore, mutation of a single allele of the Thrb gene is sufficient to drive the TSH-simulated hyperplastic thyroid follicular cells to undergo carcinogenesis. The present study suggests that the ThrbPV/+-PTU mouse model potentially could be used to gain insights into the molecular basis underlying the association between thyroid cancer and RTH seen in some affected patients.

Gene expression of T3-regulated genes in a mouse model of the human thyroid hormone resistance

Life Sciences ◽  
2017 ◽  
Vol 170 ◽  
pp. 93-99 ◽  
Author(s):  
LA Santiago ◽  
LC Faustino ◽  
GF Pereira ◽  
GE Imperio ◽  
CC Pazos-Moura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Mouse Model ◽  
Human Thyroid ◽  
Hormone Resistance ◽  
Thyroid Hormone Resistance

scholarly journals Retinoic acid-mediated down-regulation of ENO1/MBP-1 gene products caused decreased invasiveness of the follicular thyroid carcinoma cell lines

2008 ◽  
Vol 42 (3) ◽  
pp. 249-260 ◽  
Author(s):  
Bogusz Trojanowicz ◽  
Anja Winkler ◽  
Kathrin Hammje ◽  
Zhouxun Chen ◽  
Carsten Sekulla ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Thyroid Carcinoma ◽  
Cell Lines ◽  
Carcinoma Cell ◽  
Follicular Thyroid Carcinoma ◽  
Human Thyroid ◽  
Gene Products ◽  
Down Regulation ◽  
Carcinoma Cell Lines ◽  
Thyroid Carcinoma Cell

Retinoic acid (RA) acts as an anti-proliferative and redifferentiation agent in the therapy of thyroid carcinoma. Our previous studies demonstrated that pretreatment of follicular thyroid carcinoma cell lines FTC-133 and FTC-238 resulted in decreased in vitro proliferation rates and reduced tumor cell growth of xenotransplants. In addition to the previous results, we found that RA led to decreased vitality and invasiveness of FTC-133 and FTC-238 cells as they reacted with reduction of intracellular ATP levels and number of migrated cells respectively. However, the molecular mechanisms by which RA mediates these effects are not well understood. Two-dimensional (2D) screening of the proteins related to ATP metabolism and western blot analysis revealed α-enolase (ENO1) to be down-regulated in FTC-133 and FTC-238 cells after RA treatment. 2D gel detection and mass spectrometric analysis revealed that ENO1 existed as three separate protein spots of distinct pIs (ENO1–A1–A3). Comparative 2D difference gel electrophoresis analysis of fluorescently labeled protein samples of RA-treated and untreated FTC-133 demonstrated a selective down-regulation of ENO1-A1 which we identified as a phosphoprotein. RA caused the dephosphorylation of ENO1-A1. Both, RA-mediated and specific knock-down of ENO1/MBP-1 resulted in the reduction of MYC oncoprotein, and simultaneously decreased proliferation rates of FTC-133 and FTC-238 cell lines. In summary, the RA-mediated down-regulation of the ENO1 gene products and MYC oncoprotein provides a novel molecular mechanism facilitating the anti-proliferative effect of RA in human thyroid carcinoma cells and suggests new pathways for supportive RA therapies.

scholarly journals miR-146a and miR-146b promote proliferation, migration and invasion of follicular thyroid carcinoma via inhibition of ST8SIA4

Oncotarget ◽  
2017 ◽  
Vol 8 (17) ◽  
pp. 28028-28041 ◽  
Author(s):  
Wei Ma ◽  
Xuzi Zhao ◽  
Leilei Liang ◽  
Guangzhi Wang ◽  
Yanyan Li ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Follicular Thyroid Carcinoma ◽  
Migration And Invasion

scholarly journals Peritoneal Metastatic Cancer Stem Cells of Gastric Cancer with Partial Mesenchymal-Epithelial Transition and Enhanced Invasiveness in an Intraperitoneal Transplantation Model

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Xiao-Hai Song ◽  
Xin-Zu Chen ◽  
Xiao-Long Chen ◽  
Kai Liu ◽  
Wei-Han Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Mouse Model ◽  
Metastatic Cancer ◽  
Migration And Invasion ◽  
Transplanted Tumors ◽  
Mesenchymal Transition ◽  
Two Generations ◽  
Mesenchymal Epithelial Transition

Objectives. This preliminary study is aimed at enriching and isolating peritoneal metastatic cancer stem cells (pMCSCs) of gastric cancer and assessing their epithelial-mesenchymal transition (EMT) phenotype and invasiveness. Methods. Cancer stem cells of human gastric cancer (CSC-hGC) were previously isolated and transfected with green fluorescent protein and luciferase genes to validate the mouse model of peritoneal metastasis established via transplantation. The first and second generations ([G1] and [G2], respectively) of pMCSCs were isolated from intraperitoneally transplanted CSC-hGC (pMCSC-tGC) by spherical culture. CSC and EMT-related markers and regulators in the two generations of intraperitoneally transplanted tumors were examined by immunohistochemistry, immunofluorescence staining, and quantitative PCR. Cell mobility was examined by a transwell assay. Results. The nude mouse model of intraperitoneally transplanted CSC-hGC was successful in establishing sequential formation of peritoneal tumors and enrichment of pMCSCs. CD44 and CD54 were consistently expressed in the two generations of transplanted tumors. In vitro cell (migration) assays and immunocytofluorescence assays showed that in pMCSC-tGC[G2], E-cad, Survivin, and Vimentin expression was stable; α-SMA expression was decreased; and OVOL2, GRHL2, and ZEB1 expression was increased. PCR analysis indicated that in pMCSC-tGC[G2], the mRNA expression of E-cad, α-SMA, MMP9, MMP2, and Vimentin was downregulated, while that of ZEB1, OVOL2, and GRHL2 was upregulated. In vivo tumor (homing) assays and immunohistochemical assays demonstrated that in pMCSC-tGC[G2], E-cad and Snail were upregulated, while α-SMA was downregulated. The numbers of migrated and invaded pMCSC-tGC[G1] and pMCSC-tGC[G2] were significantly higher than those of CSC-hGC in migration and invasion assays. Conclusions. pMCSCs might be a specific subpopulation that can be sequentially enriched by intraperitoneal transplantation. pMCSCs exhibited a tendency towards partial mesenchymal-epithelial transition, enhancing their invasiveness during homing and the formation of peritoneal tumors. However, these preliminary findings require validation in further experiments.

Sign in / Sign up

Export Citation Format

Share Document