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Activation of tumor cell proliferation by thyroid hormone in a mouse model of follicular thyroid carcinoma.

ABSTRACT: Thyroid cancers are the most common malignancy of the endocrine system in humans. To understand the molecular genetic events underlying thyroid carcinogenesis, we have generated a mouse model that spontaneously develops follicular thyroid carcinoma similar to human thyroid cancer (Thrb(PV/PV) mouse). This mutant mouse harbors a dominant-negative mutated thyroid hormone receptor ? (denoted PV). The PV mutation was identified in a patient with resistance to thyroid hormone (TH). Thrb(PV/PV) mice exhibit highly elevated serum thyroid-stimulating hormone levels and increased TH. We have previously shown that thyroid-stimulating hormone is required, but not sufficient to induce metastatic follicular thyroid cancer in Thrb(PV/PV) mice. However, whether the elevated TH also contributes to the thyroid carcinogenesis of Thrb(PV/PV) mice was not elucidated. To understand the role of TH in thyroid carcinogenesis, we blocked the production of TH by treating Thrb(PV/PV) mice with propylthiouracil (Thrb(PV/PV)-PTU mice) and compared the development of thyroid cancer in Thrb(PV/PV)-PTU and untreated Thrb(PV/PV) mice. We found that thyroid tumor growth was reduced by ?42% in Thrb(PV/PV)-PTU mice as compared with Thrb(PV/PV) mice. Analysis by bromodeoxyuridine-nuclear labeling showed decreased incorporation of bromodeoxyuridine in thyroid tumor cells of Thrb(PV/PV)-PTU mice, indicative of decreased tumor cell proliferation. However, cleaved-caspase 3 staining showed no apparent changes in apoptosis of tumor cells in Thrb(PV/PV)-PTU mice. Molecular studies identified a marked attenuation of the PI3K-AKT-?-catenin signaling pathway that led to decreased protein levels of cyclin D2, thereby decreasing tumor cell proliferation in Thrb(PV/PV)-PTU mice. Furthermore, matrix metalloproteinase-2, a downstream target of ?-catenin and a key regulator during tumor invasion and metastasis, was also decreased. Thus, the present study uncovers a critical role of TH in promoting the thyroid carcinogenesis of Thrb(PV/PV) mice via membrane signaling events. Importantly, these findings suggest that anti-thyroid drugs could be considered as possible therapeutic agents of thyroid cancer.

SUBMITTER: Lu C

PROVIDER: S-EPMC3728834 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Activation of tumor cell proliferation by thyroid hormone in a mouse model of follicular thyroid carcinoma.

Lu C C Zhu X X Willingham M C MC Cheng S-Y SY

Oncogene 20110912 16

Thyroid cancers are the most common malignancy of the endocrine system in humans. To understand the molecular genetic events underlying thyroid carcinogenesis, we have generated a mouse model that spontaneously develops follicular thyroid carcinoma similar to human thyroid cancer (Thrb(PV/PV) mouse). This mutant mouse harbors a dominant-negative mutated thyroid hormone receptor β (denoted PV). The PV mutation was identified in a patient with resistance to thyroid hormone (TH). Thrb(PV/PV) mice e ...[more]

PMID: 21909131

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Project description:The incidence of thyroid cancer, the most frequent endocrine neoplasia, is rapidly increasing. Significant progress has recently been made in the identification of genetic lesions in thyroid cancer; however, whether inflammation contributes to thyroid cancer progression remains unknown. Using a mouse model of aggressive follicular thyroid cancer (FTC; ThrbPV/PVPten+/- mice), we aimed to elucidate a cause-effect relationship at the molecular level. The ThrbPV/PVPten+/- mouse expresses a dominantly negative thyroid hormone receptor ? (denoted as PV) and a deletion of a single allele of the Pten gene. These two oncogenic signaling pathways synergistically activate PI3K-AKT signaling to drive cancer progression as in human FTC. At the age of 5-7 weeks, thyroids of ThrbPV/PVPten+/- mice exhibited extensive hyperplasia accompanied by 77.5-fold infiltration of inflammatory monocytes as compared with normal thyroids. Global gene expression profiling identified altered expression of 2387 genes, among which 1353 were upregulated and 1034 were down-regulated. Further analysis identified markedly elevated expression of inflammation mediators and cytokines such as, Csf1r, Csf1, SPP1, Aif1, IL6, Ccl9, Ccl3, Ccl12, and Ccr2 genes and decreased expression of Kit, Ephx2, Cd163, IL15, Ccl11, and Cxcl13 genes. These changes elicited the inflammatory responses in the hyperplastic thyroid of ThrbPV/PVPten+/- mice, reflecting early events in thyroid carcinogenesis. We next tested whether attenuating the inflammatory responses could mitigate thyroid cancer progression. We treated the mice with an inhibitor of colony-stimulating factor 1 receptor (CSF1R), pexidartinib (PLX-3397; PLX). CSF1R mediates the activity of the cytokine, colony stimulating factor 1 (CSF1), in the production, differentiation, and functions of monocytes and macrophages. Treatment with PLX decreased 94% and 62% of inflammatory monocytes in the thyroid and bone marrow, respectively, versus controls. Further, PLX suppressed the expression of critical cytokine and inflammation-regulating genes such as Csf1r, SPP1 (OPN), Aif1, IL6, Ccl9, Ccl3, Ccl12, and Ccr2 (25%-80%), resulting in inhibition of 89% tumor cell proliferation, evidenced by Ki-67 immunostaining. These preclinical findings suggest that inflammation occurs in the early stage of thyroid carcinogenesis and plays a critical in cancer progression. Importantly, attenuation of inflammation by inhibitors such as PLX would be beneficial in preventing thyroid cancer.

Project description:Metastasis is the major cause of thyroid cancer-related death. However, little is known about the genes involved in the metastatic spread of thyroid carcinomas. We have created a mouse that spontaneously develops metastatic follicular thyroid carcinoma (FTC). This mouse harbors a targeted mutation (denoted TRβPV) in the thyroid hormone receptor β gene (Thrb(PV/PV) mice). Our recent studies show that the highly elevated level of thyroid stimulating hormone (TSH) in Thrb(PV/PV) mice promotes proliferation of thyroid tumor cells, but requires the collaboration of the oncogenic action of TRβPV to empower the tumor cells to undergo distant metastasis. To uncover genes destined to drive the metastatic process, we used cDNA microarrays to compare the genomic expression profile of laser capture microdissected thyroid tumor lesions of Thrb(PV/PV) mice with that of hyperplastic thyroid cells of wild-type mice having elevated TSH induced by treatment with the anti-thyroid drug propylthiouracil (WT-PTU mice). Analyses of microarray data indicated that the expressions of 150 genes were significantly altered between Thrb(PV/PV) and WT-PTU mice (87 genes had higher expression and 63 genes had lower expression in Thrb(PV/PV) mice than in WT-PTU mice). Thirty-six percent of genes with altered expression function as key regulators in metastasis. The remaining genes were involved in various cellular processes including metabolism, intracellular trafficking, transcriptional regulation, post-transcriptional modification, and cell-cell/extracellular matrix signaling. The present studies have uncovered novel genes responsible for the metastatic spread of FTC and, furthermore, have shown that the metastatic process of thyroid cancer requires effective collaboration among genes with diverse cellular functions. Importantly, the present studies indicate that the tumor cells in the primary lesions are endowed with the genes destined to promote metastasis. Thus, our study has provided new insights into the understanding of the metastatic spread of human thyroid cancer.

Project description:BackgroundFollicular thyroid carcinoma (FTC) is the second most common cancer of the thyroid and easily develops into distant metastasis. PD-L1 is known to be associated with the carcinogenesis and progression of thyroid carcinoma. Our study aimed to investigate the biological functions of PD-L1 and to identify miRNAs that were responsible for modulating the activity of PD-L1.MethodsA total of 72 patients with FTC at The Second Affiliated Hospital of Fujian Medical University were enrolled in this retrospective study. Immunohistochemical (IHC) assay was used to measure PD-L1 expression in FTC. The association between PD-L1 expression and clinicopathologic characteristics was evaluated. Bioinformatics analysis, RT-qPCR and western blotting were used to examine the relationships between miR-199a-5p, PD-L1 and Claudin-1. Cell proliferation, migration and invasion were evaluated by using CCK8 and Transwell migration and invasion assays. Target prediction and luciferase reporter assays were performed to verify the binding between miR-199a-5p and PD-L1. Rescue assay was performed to confirm whether PD-L1 downregulation abolished the inhibitory effect of miR-199a-5p.ResultsAmong 72 pairs of tumor and normal specimens, the proportion of PD-L1 positive samples was higher in FTC tissues than in normal tissues. The results of ESTIMATE and CIBERSORT illustrated that there was a positive correlation between PD-L1 expression and immune infiltration, especially regulatory T cells and M1 macrophages. Prediction of immunotherapy revealed that patients with high PD-L1 expression might benefit from immune checkpoint inhibitors. Transwell migration and invasion assays showed that PD-L1 downregulation in FTC cells could significantly inhibit cell migration and invasion. The bioinformatics analysis and luciferase activity results indicated that PD-L1 was a potential target of miR-199a-5p. Knockdown of PD-L1 reversed the miR-199a-5p inhibitor mediated promotion effect. In addition, we found that PD-L1 expression was positively correlated with Claudin-1 expression and that miR-199a-5p affected the progression of FTC cells through the negative regulation of PD-L1 and Claudin-1.ConclusionsOur study revealed that PD-L1 expression was elevated in FTC and was closely associated with tumor aggressiveness and progression. MiR-199a-5p has a functional role in the progression and metastasis of FTC by regulating PD-L1 and Claudin-1 expression.

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Activation of tumor cell proliferation by thyroid hormone in a mouse model of follicular thyroid carcinoma.

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Activation of tumor cell proliferation by thyroid hormone in a mouse model of follicular thyroid carcinoma.

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