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Carcinoma/*genetics ; Core Binding Factor Alpha 3 Subunit/*genetics ; Humans ; Thyroid Neoplasms/*genetics

No abstract available.
Fasting* ; Glucose*

BACKGROUND AND OBJECTIVES: The BRAFV600E mutation has been regarded as the leading cause of papillary thyroid cancer (PTC). However, the multi-step carcinogenic process induced by BRAFV600E has been remained to be elucidated in thyroid gland. In this study, to investigate staged development of papillary thyroid carcinoma, we observed the histo-pathological findings of thyroid gland from BRAFV600E transgenic mice with a period of 60 weeks. MATERIALS AND METHODS: We histologically inspected 3, 9, 20, 27, 39, 44, 48 and 60 week old BRAFV600E transgenic mice derived from FVB/N background mice with a bovine thyroglobulin promoter which are providing thyroid specific BRAFV600E expression. RESULTS: Thyroid glands from 3 and 9 week old BRAFV600E transgenic mice were enlarged and showed abnormal histologic feature such as distorted follicular architectures. The 20 and 27 week old BRAFV600E transgenic mice showed irregularly enlarged thyroid gland sprouting out above the carotid arteries. Thyroid gland derived from 39 week old mice showed reduced formation of intact follicular structure and increased solid area. Thyroid glands were entirely replaced by firm tumor mass composed of poorly differentiated cell at 44 weeks. Interestingly, we could observe tracheal invasion, surrounding muscle invasion in thyroid gland from 48 week old mice and detect lung metastasis in 60 week old mice. CONCLUSION: Thyroid specific expression of BRAFV600E induced staged development of thyroid cancer. This finding may support that BRAFV600E have a role in entire carcinogenic process such as tumor initiation, development and progression.
Animals ; Carcinoma ; Carotid Arteries ; Lung ; Mice ; Mice, Transgenic ; Muscles ; Neoplasm Metastasis ; Proto-Oncogene Proteins B-raf ; Thyroglobulin ; Thyroid Gland ; Thyroid Neoplasms

Thyroid cancer is one of the most common malignancies of endocrine organs, and its incidence rate has increased steadily over the past several decades. Most differentiated thyroid tumors derived from thyroid epithelial cells exhibit slow-growing cancers, and patients with these tumors can achieve a good prognosis with surgical removal and radioiodine treatment. However, a small proportion of patients present with advanced thyroid cancer and are unusually resistant to current drug treatment modalities. Thyroid tumorigenesis is a complex process that is regulated by the activation of oncogenes, inactivation of tumor suppressors, and alterations in programmed cell death. Mitochondria play an essential role during tumor formation, progression, and metastasis of thyroid cancer. Recent studies have successfully observed the mitochondrial etiology of thyroid carcinogenesis. This review focuses on the recent progress in understanding the molecular mechanisms of thyroid cancer relating to altered mitochondrial metabolism.
Carcinogenesis ; Cell Death ; Epithelial Cells ; Humans ; Incidence ; Metabolism* ; Mitochondria ; Neoplasm Metastasis ; Oncogenes* ; Prognosis ; Quality Control* ; Thyroid Gland* ; Thyroid Neoplasms*

BACKGROUND AND OBJECTIVES: Sirtuins (SIRTs) play important roles in cellular and organismal homeostasis. They have distinct gene expression patterns in various cancers; however, the relationship between SIRT expression and the progression of thyroid cancer is unclear. We investigated the expression of SIRTs in patients with papillary thyroid carcinoma (PTC) and their role as biomarkers for predicting the aggressiveness of this disease. MATERIALS AND METHODS: We used immunohistochemical staining to evaluate the expression of SIRT1 and SIRT3 in tumor specimens from 270 patients with PTC. We also evaluated the potential association between SIRT expression and diverse clinicopathological features. RESULTS: High SIRT1 expression was negatively correlated with lymphovascular invasion, central lymph node metastasis, and lateral lymph node metastasis. Multivariate analyses revealed that high SIRT1 expression was a negative independent risk factor for lateral lymph node metastasis. By contrast, high SIRT3 expression was positively correlated with locoregional recurrence. Interestingly, when patients were grouped by tumor SIRT expression patterns, the group with low SIRT1 expression and high SIRT3 expression was correlated with more aggressive cancer phenotypes including central lymph node metastasis and lateral lymph node metastasis. CONCLUSION: Our results suggest that SIRTs play dual roles in tumor progression, and the combination of decreased SIRT1 expression and increased SIRT3 expression is significantly associated with a poor prognosis in patients with PTC.
Biomarkers ; Gene Expression ; Homeostasis ; Humans ; Lymph Nodes ; Multivariate Analysis ; Neoplasm Metastasis ; Phenotype ; Prognosis ; Recurrence ; Risk Factors ; Sirtuins ; Thyroid Gland ; Thyroid Neoplasms

Paracrine interactions are imperative for the maintenance of adipose tissue intercellular homeostasis, and intracellular organelle dysfunction results in local and systemic alterations in metabolic homeostasis. It is currently accepted that mitochondrial proteotoxic stress activates the mitochondrial unfolded protein response (UPRmt) in vitro and in vivo. The induction of mitochondrial chaperones and proteases during the UPRmt is a key cell-autonomous mechanism of mitochondrial quality control. The UPRmt also affects systemic metabolism through the secretion of cell non-autonomous peptides and cytokines (hereafter, metabokines). Mitochondrial function in adipose tissue plays a pivotal role in whole-body metabolism and human diseases. Despite continuing interest in the role of the UPRmt and quality control pathways of mitochondria in energy metabolism, studies on the roles of the UPRmt and metabokines in white adipose tissue are relatively sparse. Here, we describe the role of the UPRmt in adipose tissue, including adipocytes and resident macrophages, and the interactive roles of cell non-autonomous metabokines, particularly growth differentiation factor 15, in local adipose cellular homeostasis and systemic energy metabolism.

Obesity results in an inflammatory microenvironment in adipose tissue, leading to the deterioration of tissue protective mechanisms. Although recent studies suggested the importance of type 2 immunity in an anti-inflammatory microenvironment in adipose tissue, the regulatory effects of T helper 2 (Th2) cytokines on systemic metabolic regulation are not fully understood. Recently, we identified the roles of the Th2 cytokine (interleukin 4 [IL-4] and IL-13)-induced adipokine, growth differentiation factor 15 (GDF15), in adipose tissue in regulating systemic glucose metabolism via signal transducer and activator of transcription 6 (STAT6) activation. Moreover, we showed that mitochondrial oxidative phosphorylation is required to maintain these macrophage-regulating autocrine and paracrine signaling pathways via Th2 cytokine-induced secretion of GDF15. In this review, we discuss how the type 2 immune response and Th2 cytokines regulate metabolism in adipose tissue. Specifically, we review the systemic regulatory roles of Th2 cytokines in metabolic disease and the role of mitochondria in maintenance of type 2 responses in adipose tissue homeostasis.
Adipokines ; Adipose Tissue ; Cytokines ; Glucose ; Growth Differentiation Factor 15 ; Homeostasis ; Metabolic Diseases ; Metabolism ; Mitochondria ; Obesity ; Oxidative Phosphorylation ; Paracrine Communication ; STAT6 Transcription Factor

Cancer therapies targeting genetic alterations are a topic of great interest in the field of thyroid cancer, which frequently harbors mutations in the RAS, RAF, and RET genes. Unfortunately, U.S. Food and Drug Administration-approved BRAF inhibitors have relatively low therapeutic efficacy against BRAF-mutant thyroid cancer; in addition, the cancer often acquires drug resistance, which prevents effective treatment. Recent advances in genomics and transcriptomics are leading to a more complete picture of the range of mutations, both driver and messenger, present in thyroid cancer. Furthermore, our understanding of cancer suggests that oncogenic mutations drive tumorigenesis and induce rewiring of cancer cell metabolism, which promotes survival of mutated cells. Synthetic lethality (SL) is a method of neutralizing mutated genes that were previously considered untargetable by traditional genotype-targeted treatments. Because these metabolic events are specific to cancer cells, we have the opportunity to develop new therapies that target tumor cells specifically without affecting healthy tissue. Here, we describe developments in metabolism-based cancer therapy, focusing on the concept of metabolic SL in thyroid cancer. Finally, we discuss the essential implications of metabolic reprogramming and its role in the future direction of SL for thyroid cancer.