1.Development of Metabolic Synthetic Lethality and Its Implications for Thyroid Cancer
Sang-Hyeon JU ; Seong Eun LEE ; Yea Eun KANG ; Minho SHONG
Endocrinology and Metabolism 2022;37(1):53-61
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.
3.Toward Systems-Level Metabolic Analysis in Endocrine Disorders and Cancer
Aliya LAKHANI ; Da Hyun KANG ; Yea Eun KANG ; Junyoung O. PARK
Endocrinology and Metabolism 2023;38(6):619-630
Metabolism is a dynamic network of biochemical reactions that support systemic homeostasis amidst changing nutritional, environmental, and physical activity factors. The circulatory system facilitates metabolite exchange among organs, while the endocrine system finely tunes metabolism through hormone release. Endocrine disorders like obesity, diabetes, and Cushing’s syndrome disrupt this balance, contributing to systemic inflammation and global health burdens. They accompany metabolic changes on multiple levels from molecular interactions to individual organs to the whole body. Understanding how metabolic fluxes relate to endocrine disorders illuminates the underlying dysregulation. Cancer is increasingly considered a systemic disorder because it not only affects cells in localized tumors but also the whole body, especially in metastasis. In tumorigenesis, cancer-specific mutations and nutrient availability in the tumor microenvironment reprogram cellular metabolism to meet increased energy and biosynthesis needs. Cancer cachexia results in metabolic changes to other organs like muscle, adipose tissue, and liver. This review explores the interplay between the endocrine system and systems-level metabolism in health and disease. We highlight metabolic fluxes in conditions like obesity, diabetes, Cushing’s syndrome, and cancers. Recent advances in metabolomics, fluxomics, and systems biology promise new insights into dynamic metabolism, offering potential biomarkers, therapeutic targets, and personalized medicine.
4.The Role of Circulating Slit2, the One of the Newly Batokines, in Human Diabetes Mellitus.
Yea Eun KANG ; Sorim CHOUNG ; Ju Hee LEE ; Hyun Jin KIM ; Bon Jeong KU
Endocrinology and Metabolism 2017;32(3):383-388
BACKGROUND: Slit2 is a new secreted protein from adipose tissue that improves glucose hemostasis in mice; however, there is no study about the serum levels and precise role of Slit2 in human. The aim of this study is to explore the serum level of Slit2 in human, and to identify the role of Slit2 in diabetes mellitus (DM). METHODS: The participants of this study consist of 38 subjects with newly diagnosed DM, and 75 healthy subjects as a control group. Serum Slit2 levels were measured using an enzyme-linked immunosorbent assay. Relationship between circulating Slit2 and diabetic related factors was investigated in diabetic group compared with non-diabetic group. Additionally, the correlations between the serum level of Slit2 and diverse metabolic parameters were analyzed. RESULTS: Circulating Slit2 level was more decreased in diabetic group than in control group, but there was no significant difference statistically. Interestingly, serum levels of Slit2 were significantly negatively correlated to the serum concentrations of fasting glucose (coefficient r=–0.246, P=0.008), the serum concentrations of postprandial glucose (coefficient r=–0.233, P=0.017), and glycosylated hemoglobin (HbA1c; coefficient r=–0.357, P<0.001). CONCLUSION: From our study, the first report of circulating Slit2 levels in human, circulating Slit2 level significantly negatively correlated with serum glucose and HbA1c. Our results suggest that the circulating Slit2 may play a role in maintainence of glucose homeostasis in human, even though exact contribution and mechanism are not yet known.
Adipokines
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Adipose Tissue
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Adipose Tissue, Brown
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Animals
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Blood Glucose
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Diabetes Mellitus*
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Enzyme-Linked Immunosorbent Assay
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Fasting
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Glucose
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Healthy Volunteers
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Hemoglobin A, Glycosylated
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Hemostasis
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Homeostasis
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Humans*
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Mice
5.Treatment with Gefitinib, an Epidermal Growth Factor Receptor Inhibitor, Decreases Serum Cholesterol in Patients with Lung Cancer
Yea Eun KANG ; Ji Min KIM ; Kyong Hye JOUNG ; Hyun Jin KIM ; Bon Jeong KU
Korean Journal of Obesity 2016;25(4):233-239
BACKGROUND: Statins are used to treat hypercholesterolemia; however, major cardiovascular events are decreased only 30% by statin treatment. Treatment with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been reported to decrease serum glucose levels and improved insulin sensitivity in mice and humans, but there was no study in serum cholesterol levels. This study examined the effect of gefitinib, an EGFR tyrosine kinase inhibitor, on cholesterol metabolism in humans. METHODS: We retrospectively reviewed the medical records of 299 patients with primary lung cancer treated with gefitinib for ≥1 month and 72 patients with other treatments. Serum cholesterol, serum triglycerides, and body mass index were measured before and after treatment. The changes in serum cholesterol, serum triglycerides, and body mass index were compared between the gefitinib treatment group and the control group and were also analyzed according to the presence or absence of EGFR mutations. RESULTS: Serum cholesterol levels decreased significantly from 178.9 to 164.4 mg/dL after 1-month of gefitinib treatment. A total of 54 of the 299 patients underwent examination for the presence of the EGFR mutations. Serum cholesterol was significantly decreased in the group with the activating EGFR mutation (Δ=21.3 mg/dL) compared to that of those without the EGFR mutation (Δ=-3.1 mg/dL) after treatment with gefitinib. In contrast, there was no significantly difference between the two groups in control patients. CONCLUSION: Treatment with gefitinib decreased serum cholesterol in lung cancer patients, particularly in those with activating mutations in EGFR. These data suggest that EGFR tyrosine kinase inhibitors provide a novel and attractive strategy for the treatment of hypercholesterolemia.
Animals
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Blood Glucose
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Body Mass Index
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Cholesterol
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Epidermal Growth Factor
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Hypercholesterolemia
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Insulin Resistance
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Lung Neoplasms
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Lung
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Medical Records
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Metabolism
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Mice
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Protein-Tyrosine Kinases
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Receptor, Epidermal Growth Factor
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Retrospective Studies
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Triglycerides
6.Regulation of Systemic Glucose Homeostasis by T Helper Type 2 Cytokines
Yea Eun KANG ; Hyun Jin KIM ; Minho SHONG
Diabetes & Metabolism Journal 2019;43(5):549-559
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
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Adipose Tissue
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Cytokines
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Glucose
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Growth Differentiation Factor 15
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Homeostasis
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Metabolic Diseases
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Metabolism
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Mitochondria
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Obesity
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Oxidative Phosphorylation
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Paracrine Communication
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STAT6 Transcription Factor
7.Malignant intercostal psammomatous melanotic schwannoma in a patient with Carney complex.
Yea Eun KANG ; Jin Ok JEONG ; Kyung Hee KIM ; Chang Seok KI ; Hyun Jin KIM
The Korean Journal of Internal Medicine 2018;33(6):1256-1257
No abstract available.
Carney Complex*
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Humans
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Neurilemmoma*
8.Prognostic Significance of Sirtuins Expression in Papillary Thyroid Carcinoma
Yea Eun KANG ; Minho SHONG ; Jin Man KIM ; Bon Seok KOO
International Journal of Thyroidology 2018;11(2):143-151
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
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Gene Expression
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Homeostasis
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Humans
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Lymph Nodes
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Multivariate Analysis
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Neoplasm Metastasis
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Phenotype
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Prognosis
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Recurrence
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Risk Factors
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Sirtuins
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Thyroid Gland
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Thyroid Neoplasms
10.Metabolic Reprogramming in Thyroid Cancer
Sang-Hyeon JU ; Minchul SONG ; Joung Youl LIM ; Yea Eun KANG ; Hyon-Seung YI ; Minho SHONG
Endocrinology and Metabolism 2024;39(3):425-444
Thyroid cancer is a common endocrine malignancy with increasing incidence globally. Although most cases can be treated effectively, some cases are more aggressive and have a higher risk of mortality. Inhibiting RET and BRAF kinases has emerged as a potential therapeutic strategy for the treatment of thyroid cancer, particularly in cases of advanced or aggressive disease. However, the development of resistance mechanisms may limit the efficacy of these kinase inhibitors. Therefore, developing precise strategies to target thyroid cancer cell metabolism and overcome resistance is a critical area of research for advancing thyroid cancer treatment. In the field of cancer therapeutics, researchers have explored combinatorial strategies involving dual metabolic inhibition and metabolic inhibitors in combination with targeted therapy, chemotherapy, and immunotherapy to overcome the challenge of metabolic plasticity. This review highlights the need for new therapeutic approaches for thyroid cancer and discusses promising metabolic inhibitors targeting thyroid cancer. It also discusses the challenges posed by metabolic plasticity in the development of effective strategies for targeting cancer cell metabolism and explores the potential advantages of combined metabolic targeting.