A selective cyclin-dependent kinase 4, 6 dual inhibitor, Ribociclib (LEE011) inhibits cell proliferation and induces apoptosis in aggressive thyroid cancer

Lee, Hyun Joo,Lee, Woo Kyung,Kang, Chan Woo,Ku, Cheol Ryong,Cho, Yoon Hee,Lee, Eun Jig Elsevier 2018 Cancer letters Vol.417 No.-

<P><B>Abstract</B></P> <P>The RB-E2F1 pathway is an important mechanism of cell-cycle control, and deregulation of this pathway is one of the key factors contributing to tumorigenesis. Cyclin-dependent kinases (CDKs) and Cyclin D have been known to increase in aggressive thyroid cancer. However, there has been no study to investigate effects of a selective CDK 4/6 inhibitor, Ribociclib (LEE011), in thyroid cancer. Performing Western blotting, we found that RB phosphorylation and the expression of Cyclin D are significantly higher in papillary thyroid cancer (PTC) cell lines as well as anaplastic thyroid cancer (ATC) cell lines, compared with normal thyroid cell line and follicular thyroid cancer cell line. LEE011 dose-dependently inhibited RB phosphorylation and also decreased the expressions of its target genes such as <I>FOXM1, Cyclin A1,</I> and <I>Myc</I> in ATC. Furthermore, LEE011 induced cell cycle arrest in G0-G1 phase and cell apoptosis, and inhibited cell proliferation in ATC. Consistently, oral administration of LEE011 to ATC xenograft models strongly inhibited tumor growth with decreased expressions of pRB, pAKT and Ki-67, and also significantly increased tumor cell apoptosis. Taken together, our data support the rationale for clinical development of the CDK4/6 inhibitor as a therapy for patients with aggressive thyroid cancer.</P> <P><B>Highlights</B></P> <P> <UL> <LI> pRB and Cyclin D were expressed high in aggressive thyroid cancer. </LI> <LI> LEE011 suppressed pRB and also decreased the expressions of its target genes in ATC. </LI> <LI> LEE011 induced cell cycle G1 arrest and apoptosis, and inhibited cell proliferation. </LI> <LI> LEE011 inhibited in vivo tumor growth with decreased expressions of pRB and Ki-67. </LI> <LI> We could explain the anticancer effects with the RB-E2F pathway. </LI> </UL> </P>

노인의 갑상선기능저하증에 대한 임상적 연구

정윤석,남문석,이은직,김경래,이현철,김현승,허갑범 한국노화학회 1993 한국노화학회지 Vol.3 No.1

Glycated albumin is a useful glycation index for monitoring fluctuating and poorly controlled type 2 diabetic patients

Lee, Eun Young,Lee, Byung-Wan,Kim, Daham,Lee, Yong-ho,Kim, Kwang Joon,Kang, Eun Seok,Cha, Bong-Soo,Lee, Eun Jig,Lee, Hyun Chul Springer-Verlag 2011 Acta diabetologica Vol.48 No.2

내장지방/골격근 비와 인슐린 저항성과의 연관성

이지현,송영득,차봉수,남수연,원영준,신민정,이종호,이은직,임승길,김경래,이현철,허갑범 대한당뇨병학회 1996 Diabetes and Metabolism Journal Vol.20 No.4

A Metabolic Phenotype Based on Mitochondrial Ribosomal Protein Expression as a Predictor of Lymph Node Metastasis in Papillary Thyroid Carcinoma

Lee, Jandee,Seol, Mi-Youn,Jeong, Seonhyang,Lee, Cho Rok,Ku, Cheol Ryong,Kang, Sang-Wook,Jeong, Jong Ju,Shin, Dong Yeob,Nam, Kee-Hyun,Lee, Eun Jig,Chung, Woong Youn,Jo, Young Suk Wolters Kluwer Health 2015 Medicine Vol.94 No.2

<▼1><P>Supplemental Digital Content is available in the text</P></▼1><▼2><P><B>Abstract</B></P><P>Metabolic reprogramming has been regarded as an essential component of malignant transformation. However, the clinical significance of metabolic heterogeneity remains poorly characterized.</P><P>The aim of this study was to characterize metabolic heterogeneity in thyroid cancers via the analysis of the expression of mitochondrial ribosomal proteins (MRPs) and genes involved in oxidative phosphorylation (OxPhos), and investigate potential prognostic correlations.</P><P>Gene set enrichment analysis (GSEA) verified by reverse transcription polymerase chain reaction and gene network analysis was performed using public repository data. Cross-sectional observational study was conducted to classify papillary thyroid cancer (PTC) by the expression of MRP L44 (MRPL44) messenger RNA (mRNA), and to investigate the clinicopathological features.</P><P>GSEA clearly showed that the expression of OxPhos and MRP gene sets was significantly lower in primary thyroid cancer than in matched normal thyroid tissue. However, 8 of 49 primary thyroid tumors (16.3%) in the public repository did not show a reduction in OxPhos mRNA expression. Remarkably, strong positive correlations between MRPL44 expression and those of OxPhos and MRPs such as reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) 1 α subcomplex, 5; succinate dehydrogenase complex, subunit D; cytochrome c, somatic; adenosine triphosphate synthase, H+ transporting, mitochondrial Fo complex, subunit C1 (subunit 9); and MRP S5 (MRPS5) (<I>P</I> < 0.0001) were clearly denoted, suggesting that MRPL44 is a representative marker of OxPhos and MRP expressions. In laboratory experiments, metabolic heterogeneity in oxygen consumption, extracellular acidification rates (ECARs), and amounts of OxPhos complexes were consistently observed in BCPAP, TPC1, HTH-7, and XTC.UC1 cell lines. In PTCs, metabolic phenotype according to OxPhos amount defined by expression of MRPL44 mRNA was significantly related to lymph node metastasis (LNM) (<I>P</I> < 0.001). Furthermore, multivariate analysis clearly indicated that expression of MRPL44 is associated with an increased risk of lateral neck LNM (odds ratio 9.267, 95% confidence interval 1.852–46.371, <I>P</I> = 0.007).</P><P>MRPL44 expression may be a representative marker of metabolic phenotype according to OxPhos amount and a useful predictor of LNM.</P></▼2>

뇌하수체에 전이된 십이지장 팽대부주위 선암종 1 예

이경미,배희동,허갑범,이현철,임승길,이은직,김경래,안광진,정윤석,이관식,신은택 대한내분비학회 1993 Endocrinology and metabolism Vol.8 No.1

Pituitary metastais is a rare condition of distant metastasis of systemic cancer. Pituitary metastasis may present headache, hypopituitarism, and diabetes insipidus resulting from metastatic site. We report a 42 year-old man with pituitary metastasis from periampullary adenocarcinoma who developed diplopea follwing headache and importence. He also had widespreak lymph node metastasis. Diagnosis was made by endoscopy with biopsy, abdominal ultrasonogram, abdominal CT scan, and brain CT scan. Brain CT scan showed tumor in the pituitary gland with invasion into sphenoid bone and cavernous sinus. Light microscopic fingdings revealed moderately differentiated adenocarcinoma in periampullary mass, and metastatic adenocarcinoma in the cevical lymph node. The combined pituitary stimulation test showed decreased reserve capacity of pituitary hormones. We report a case of pituitary metastasis from periampullary adenocarcinoma with the revies of the literature.(J Kor Endocrino 8:88~93, 1993)

KSR1 is coordinately regulated with Notch signaling and oxidative phosphorylation in thyroid cancer

Lee, Jandee,Seol, Mi-Youn,Jeong, Seonhyang,Kwon, Hyeong Ju,Lee, Cho Rok,Ku, Cheol Ryong,Kang, Sang-Wook,Jeong, Jong Ju,Shin, Dong Yeob,Nam, Kee-Hyun,Lee, Eun Jig,Chung, Woong Youn,Jo, Young Suk Journal of Endocrinology (Ltd. by Guarantee) 2015 Journal of molecular endocrinology Vol.54 No.2

<P>Kinase suppressor of RAS1 (KSR1) is a scaffold protein implicated in RAS-mediated RAF activation. However, the molecular function of KSR in papillary thyroid cancer (PTC) is unknown. Thus, this study aimed to characterize the role of KSR1 in patients with PTC. qRT-PCR and immunohistochemistry (IHC) revealed inter-tumor heterogeneities in the expression of KSR1 in PTC tissues. Interestingly, BRAFV600E-positive PTC showed higher <I>KSR1</I> mRNA expression than BRAFV600E-negative PTC (<I>P</I><0.001). Gene Set Enrichment Analysis (GSEA) using public repositories showed that high KSR1 expression coordinately upregulated Notch signaling (nominal <I>P</I>=0.019, false discovery rate (FDR) <I>q</I>-value=0.165); this finding was supported by GeneNetwork analysis, indicating that <I>KSR1</I> expression is positively correlated with <I>NOTCH1</I> expression (<I>ρ</I>=0.677, <I>P</I>=6.15×10<SUP>−9</SUP>). siRNA against KSR1 (siKSR1) significantly decreased ERK phosphorylation induced by BRAFV600E, resulting in reduced expression of <I>NOTCH1</I> and <I>HES1</I>, targets of Notch signaling. GSEA revealed that high KSR1 expression was also associated with downregulation of genes related to oxidative phosphorylation (OxPhos). Consistent with this, electron microscopy showed that PTCs with high KSR1 expression exhibited structural defects of the mitochondrial cristae. Furthermore, siKSR1-transfected BCPAP and 8505C cells generated fewer colonies in colony-forming assays. In addition, GSEA showed that high expression of KSR2 and connector enhancer of KSR1 (CNKSR1) also coordinately upregulated Notch signaling (KSR2: nominal <I>P</I>=0.0097, FDR <I>q</I>-value=0.154 and CNKSR1: nominal <I>P</I><0.0001, FDR <I>q</I>-value=0.00554), and high CNKSR2 was associated with downregulation of the OxPhos gene set (nominal <I>P</I><0.0001, FDR <I>q</I>-value <0.0001). In conclusion, KSR1 is coordinately regulated with Notch signaling and OxPhos in PTC, because its scaffold function might be required to sustain the proliferative signaling and metabolic remodeling associated with this type of cancer.</P>

Adenoviral vector-mediated glucagon-like peptide 1 gene therapy improves glucose homeostasis in Zucker diabetic fatty rats

Lee, Yongho,Kwon, Mi Kyong,Kang, Eun Seok,Park, Young Mi,Choi, Seung Ho,Ahn, Chul Woo,Kim, Kyung Sub,Park, Chul Won,Cha, Bong Soo,Kim, Sung Wan,Sung, Je Kyung,Lee, Eun Jig,Lee, Hyun Chul John Wiley Sons, Ltd. 2008 The journal of gene medicine Vol.10 No.3

<B>Background</B><P>Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone that plays an important role in glucose homeostasis. Its functions include glucose-stimulated insulin secretion, suppression of glucagon secretion, deceleration of gastric emptying, and reduction in appetite and food intake. Despite the numerous antidiabetic properties of GLP-1, its therapeutic potential is limited by its short biological half-life due to rapid enzymatic degradation by dipeptidyl peptidase IV. The present study aimed to demonstrate the therapeutic effects of constitutively expressed GLP-1 in an overt type 2 diabetic animal model using an adenoviral vector system.</P><B>Methods</B><P>A novel plasmid (pAAV-ILGLP-1) and recombinant adenoviral vector (Ad-ILGLP-1) were constructed with the cytomegalovirus promoter and insulin leader sequence followed by GLP-1(7–37) cDNA.</P><B>Results</B><P>The results of an enzyme-linked immunosorbent assay showed significantly elevated levels of GLP-1(7–37) secreted by human embryonic kidney cells transfected with the construct containing the leader sequence. A single intravenous administration of Ad-ILGLP-1 into 12-week-old Zucker diabetic fatty (ZDF) rats, which have overt type 2 diabetes mellitus (T2DM), achieved near normoglycemia for 3 weeks and improved utilization of blood glucose in glucose tolerance tests. Circulating plasma levels of GLP-1 increased in GLP-1-treated ZDF rats, but diminished 21 days after treatment. When compared with controls, Ad-ILGLP-1-treated ZDF rats had a lower homeostasis model assessment for insulin resistance score indicating amelioration in insulin resistance. Immunohistochemical staining showed that cells expressing GLP-1 were found in the livers of GLP-1-treated ZDF rats.</P><B>Conclusions</B><P>These data suggest that GLP-1 gene therapy can improve glucose homeostasis in fully developed diabetic animal models and may be a promising treatment modality for T2DM in humans. Copyright © 2007 John Wiley & Sons, Ltd.</P>

Treatment of upper eyelid retraction related to thyroid-associated ophthalmopathy using subconjunctival triamcinolone injections.

Lee, Sung Jun,Rim, Tyler Hyung Taek,Jang, Sun Young,Kim, Chan Yun,Shin, Dong Yeob,Lee, Eun Jig,Lee, Sang Yeul,Yoon, Jin Sook Springer-Verlag 2013 Graefe’s archive for clinical and experimental oph Vol.251 No.1

<P>To evaluate the efficacy of subconjunctival triamcinolone injection for treating upper eyelid retraction caused by thyroid-associated ophthalmopathy (TAO).</P>

Aberrant Expression of COT Is Related to Recurrence of Papillary Thyroid Cancer

Lee, Jandee,Jeong, Seonhyang,Park, Jae Hyun,Lee, Cho Rok,Ku, Cheol Ryong,Kang, Sang-Wook,Jeong, Jong Ju,Nam, Kee-Hyun,Shin, Dong Yeob,Lee, Eun Jig,Chung, Woong Youn,Jo, Young Suk Williams & Wilkins Co 2015 Medicine Vol.94 No.6

<▼1><P>Supplemental Digital Content is available in the text</P></▼1><▼2><P><B>Abstract</B></P><P>Aberrant expression of Cancer Osaka Thyroid Oncogene mitogen-activated protein kinase kinase kinase 8 (COT) (MAP3K8) is a driver of resistance to B-RAF inhibition. However, the de novo expression and clinical implications of COT in papillary thyroid cancer (PTC) have not been investigated.</P><P>The aim of this study is to investigate the expression of A-, B-, C-RAF, and COT in PTC (n = 167) and analyze the clinical implications of aberrant expression of these genes.</P><P>Quantitative polymerase chain reaction (qPCR) and immunohistochemical staining (IHC) were performed on primary thyroid cancers. Expression of COT was compared with clinicopathological characteristics including recurrence-free survival. Datasets from public repository (NCBI) were subjected to Gene Set Enrichment Analysis (GSEA).</P><P>qPCR data showed that the relative mRNA expression of <I>A-</I>, <I>B-</I>, <I>C-RAF</I> and <I>COT</I> of PTC were higher than normal tissues (all <I>P</I> < 0.01). In addition, the expression of COT mRNA in PTC showed positive correlation with A- (<I>r</I> = 0.4083, <I>P</I> < 0.001), B- (<I>r</I> = 0.2773, <I>P</I> = 0.0003), and C-RAF (<I>r</I> = 0.5954, <I>P</I> < 0.001). The mRNA expressions of A-, B,- and C-RAF were also correlated with each other (all <I>P</I> < 0.001). In IHC, the staining intensities of B-RAF and COT were higher in PTC than in normal tissue (<I>P</I> < 0.001). Interestingly, moderate-to-strong staining intensities of B-RAF and COT were more frequent in B-RAF<SUP>V600E</SUP>-positive PTC (<I>P</I> < 0.001, <I>P</I> = 0.013, respectively). In addition, aberrant expression of COT was related to old age at initial diagnosis (<I>P</I> = 0.045) and higher recurrence rate (<I>P</I> = 0.025). In multivariate analysis, tumor recurrence was persistently associated with moderate-to-strong staining of COT after adjusting for age, sex, extrathyroidal extension, multifocality, T-stage, N-stage, TNM stage, and B-RAF<SUP>V600E</SUP> mutation (odds ratio, 4.662; 95% confidence interval 1.066 − 21.609; <I>P</I> = 0.045). Moreover, moderate-to-strong COT expression in PTC was associated with shorter recurrence-free survival (mean follow-up duration, 14.2 ± 4.1 years; <I>P</I> = 0.0403). GSEA indicated that gene sets related to B-RAF-RAS (<I>P</I> < 0.0001, false discovery rate [FDR] <I>q</I>-value = 0.000) and thyroid differentiation (<I>P</I> = 0.048, FDR <I>q</I>-value = 0.05) scores were enriched in lower COT expression group and gene sets such as T-cell receptor signaling pathway and Toll-like receptor signaling pathway are coordinately upregulated in higher COT expression group (both, <I>P</I> < 0.0001, FDR <I>q</I>-value = 0.000).</P><P>Aberrant expression of A-, B-, and C-RAF, and COT is frequent in PTC; increased expression of COT is correlated with recurrence of PTC.</P></▼2>