Cereblon Maintains Synaptic and Cognitive Function by Regulating BK Channel

Choi, Tae-Yong,Lee, Seung-Hyun,Kim, Yoon-Jung,Bae, Jae Ryul,Lee, Kwang Min,Jo, Youhwa,Kim, Soo-Jeong,Lee, A-Ram,Choi, Sekyu,Choi, La-Mee,Bang, Sunhoe,Song, Mi-Ryoung,Chung, Jongkyeong,Lee, Kyung Jin,K The Society 2018 The Journal of neuroscience Vol.38 No.14

<P>Mutations in the cereblon (CRBN) gene cause human intellectual disability, one of the most common cognitive disorders. However, the molecular mechanisms of CRBN-related intellectual disability remain poorly understood. We investigated the role of CRBN in synaptic function and animal behavior using male mouse and Drosophila models. Crbn knock-out (KO) mice showed normal brain and spine morphology as well as intact synaptic plasticity; however, they also exhibited decreases in synaptic transmission and presynaptic release probability exclusively in excitatory synapses. Presynaptic function was impaired not only by loss of CRBN expression, but also by expression of pathogenic CRBN mutants (human R419X mutant and Drosophila G552X mutant). We found that the BK channel blockers paxilline and iberiotoxin reversed this decrease in presynaptic release probability in Crbn KO mice. In addition, paxilline treatment also restored normal cognitive behavior in CrbnKOmice. These results strongly suggest that increased BK channel activity is the pathological mechanism of intellectual disability in CRBN mutations.</P>

Expression of Bmi-1 protein in tumor tissues is associated with favorable prognosis in breast cancer patients.

Choi, Young Jin,Choi, Yoon La,Cho, Eun Yoon,Shin, Young Kee,Sung, Ki Woong,Hwang, Yu Kyeong,Lee, Sang Jin,Kong, Gu,Lee, Jeong Eon,Kim, Jee Soo,Kim, Jung Han,Yang, Jung-Hyun,Nam, Seok Jin M. Nijhoff ; Kluwer Academic Publishers 2009 Breast cancer research and treatment Vol.113 No.1

<P>Abnormal expression of the cell cycle regulatory protein Bmi-1 has been studied in breast cancer, but the clinical relevance has not been fully elucidated. We studied the expression of Bmi-1 protein in breast cancer patients to define its clinical significance in breast cancer.</P>

Diagnostic approach for intra-abdominal and retroperitoneal mass

Yoon La Choi 대한종양외과학회 2020 대한임상종양학회 학술대회지 Vol.2020 No.7

MMP11 and CD2 as novel prognostic factors in hormone receptor-negative, HER2-positive breast cancer

Han, Jinil,Choi, Yoon-La,Kim, Haein,Choi, Jun Young,Lee, Se Kyung,Lee, Jeong Eon,Choi, Joon-Seok,Park, Sarah,Choi, Jong-Sun,Kim, Young Deug,Nam, Seok Jin,Nam, Byung-Ho,Kwon, Mi Jeong,Shin, Young Kee Springer US 2017 Breast cancer research and treatment Vol.164 No.1

<P><B>Purpose</B></P><P>More accurate prediction of patient outcome based on molecular subtype is required to identify patients who will benefit from specific treatments.</P><P><B>Methods</B></P><P>We selected novel 16 candidate prognostic genes, including 10 proliferation-related genes (p-genes) and 6 immune response-related genes (i-genes), from the gene list identified in our previous study. We then analyzed the association between their expression, measured by quantitative real-time reverse transcription-PCR in formalin-fixed, paraffin-embedded tissues, and clinical outcome in 819 breast cancer patients according to molecular subtype.</P><P><B>Results</B></P><P>The prognostic significance of clinical and gene variables varied according to the molecular subtype. Univariate analysis showed that positive lymph node status was significantly correlated with the increased risk of distant metastasis in all subtypes except the hormone receptor-negative, HER2-positive (HR−/HER2<B>+</B>) subtype. Most p-genes were significantly associated with poor prognosis in patients with the HR<B>+</B>/HER2− subtype, whereas i-genes correlated with a favorable outcome in patients with HR−/HER2<B>+</B> breast cancer. In HR−/HER2+ breast cancer, four genes (three i-genes <I>BTN3A2</I>, <I>CD2</I>, and <I>TRBC1</I> and the p-gene <I>MMP11</I>) were significantly associated with distant metastasis-free survival (DMFS). A new prognostic model for HR−/HER2+ breast cancer based on the expression of <I>MMP11</I> and <I>CD2</I> was developed and the DMFS for patients in the high-risk group according to our model was significantly lower than that for those in the low-risk group. Multivariate analyses revealed that our risk score is an independent prognostic factor for DMFS. Moreover, C-index showed that our risk score has a superior prognostic performance to traditional clinicopathological factors.</P><P><B>Conclusions</B></P><P>Our new prognostic model for HR−/HER2+ breast cancer provides more accurate information on the risk of distant metastasis than traditional clinical prognostic factors and may be used to identify patients with a good prognosis in this aggressive subtype of breast cancer.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1007/s10549-017-4234-4) contains supplementary material, which is available to authorized users.</P>

Development of orthotopic patient-derived tumor xenograft models in endometrial cancer

( Hyun-jin Choi ),( Eun Jin Heo ),( Young Jae Cho ),( Ji Eun Hong ),( Hye-kyung Jeon ),( Doo-yi Oh ),( Yoon-la Choi ),( Sangyong Song ),( Jung-joo Choi ),( Yoo-young Lee ),( Chel Hun Choi ),( Tae-joon 대한산부인과학회 2016 대한산부인과학회 학술대회 Vol.102 No.-

목적: To evaluate orthotopic xenografting of endometrial cancer(EM Ca) in mice for development of novel translational research platform in endometrial cancer. 방법: Fresh surgical specimens were taken from patients with EM Ca after surgery at Department of Obstetrics and Gynecology, Samsung Medical Center, Seoul, Korea between December, 2011 to February, 2016. We successfully established PDXs by orthotopic and subrenal capsule implantation of patient’s EM Ca tissues into female BALB/C-nude mice. The subrenal capsule implatation method were that pieces of EM Ca specimens from patients were meticulosely grafted in the subrenal capsule. Mean while, estrogen preconditioning was done for orthotopic implatation by given a daily s.c injection of 0.1μg estradial for three days. After then, pieces of EM Ca specimens from patients were meticulosly grafted in the enlarged mice’s uterus. The H&E staining, short tandem repeat, array comparative genomic hybridization, human and mouse albumin test and cancer panel were conducted to verifythe histopathologic and genetic similarity between the PDXs and primary patient’s tissues. 결과: Orthotopic PDX engraftment rate were sucessful in 100% (3/3 cases). While, Successful rate of subrenal capsule implantation method was 55.6% (10/18 cases). In orthotopic PDXs, median duration of first generation of PDX develoment from implantation of patient’s tissues was 5.43month (range: 0.83-6.63 month). And, in subrenal capsule implantation PDXs, median duration of first generation was 5.05month (range : 4.17-9.33 month). Both methods were proved to preserve histopathologic and genetic silimarity between PDXs and the primary patient’s tissues. 결론: The PDXs for endometiral cancer with histopathologic and genetic stability can be efficiently developed by an orthotopic implantation method rather than a subrenal capsule implantation method. This method can a promising platform for conducting translational research and future precision medicine in endomerial cancer.

Establishment of Primary Xenograft Model from Newly Characterized Patient Extrauterine Carcinosarcoma

Hyun Joo Lee,Hye-Jung Choi,Heung-Mo Yang,You Min Kim,Yoon-La Choi,Jeeyun Lee,Dongil Chio,BoKyung Kim,Yoon-La Choi,Sung Joo Kim 대한종양외과학회 2014 대한임상종양학회 학술대회지 Vol.2014 No.3

Prevalence of the <i>CTNNB1</i> mutation genotype in surgically resected fibromatosis of the breast

Kim, Taeeun,Jung, Eun Ah,Song, Ji Young,Roh, Ji Hyeon,Choi, Jong Sun,Kwon, Jee Eun,Kang, So Young,Cho, Eun Yoon,Shin, Jung Hee,Nam, Suk‐,Jin,Yang, Jung Hyun,Choi, Yoon‐,La Blackwell Publishing Ltd 2012 Histopathology Vol.60 No.2

<P>Kim T, Jung E A, Song J Y, Roh J H, Choi J S, Kwon J E, Kang S Y, Cho E Y, Shin J H, Nam S‐J, Yang J H & Choi Y‐L 
(2012) <I>Histopathology</I>?<B>60,</B> 347–356 
<B>Prevalence of the <I>CTNNB1</I> mutation genotype in surgically resected fibromatosis of the breast</B></P><P><B>Aims: </B> To investigate <I>CTNNB1</I> mutation and β‐catenin expression in resected breast fibromatosis and to identify potential molecular markers of fibromatosis of the breast.</P><P><B>Methods and results: </B> We selected 12 patients with fibromatosis of the breast who underwent surgical resection and were confirmed by histological examination. Ultrasonography findings for 10 patients were reviewed and only two cases were suspicious for fibromatosis on imaging. On core needle biopsy for pre‐operative diagnoses, only three cases were histologically suspicious for fibromatosis. Mutations in exon 3 of <I>CTNNB1</I> were detected by direct DNA sequencing in nine (75.0%) cases: all were c.121G>A (p.T41A), which was much more frequent in breast fibromatoses than in other soft tissue lesions. Nuclear β‐catenin expression was observed in all cases and the level of expression was higher in cases with mutation. In eight of nine cases, the matched biopsy specimen showed the same <I>CTNNB1</I> mutation status as the pre‐operative specimen.</P><P><B>Conclusions: </B> In the majority of cases, clinical presentation and breast imaging are highly suspicious for carcinoma. Definitive pre‐operative pathological diagnosis by core needle biopsy is difficult. <I>CTNNB1</I> mutation and nuclear β‐catenin expression are frequently detected in sporadic breast fibromatoses, suggesting their potential as a useful tool to distinguish breast fibromatoses from other neoplasms.</P>

Prediction of Subclinical Coronary Artery Disease With Breast Arterial Calcification and Low Bone Mass in Asymptomatic Women : Registry for the Women Health Cohort for the BBC Study

Yoon, Yeonyee E.,Kim, Kyoung Min,Han, Jong Soo,Kang, Si-Hyuck,Chun, Eun Ju,Ahn, Soyeon,Kim, Sun Mi,Choi, Sang Il,Yun, Bo La,Suh, Jung-Won American College of Cardiology 2019 JACC CARDIOVASCULAR IMAGING Vol.12 No.7

<P><B>Graphical abstract</B></P><P>[Figure]</P><P><B>Abstract</B></P><P><B>Objectives</B></P><P>This study sought to determine whether evaluations of breast arterial calcification (BAC) and low bone mass (LBM) could improve the ability to predict subclinical coronary artery disease (CAD) in asymptomatic women.</P><P><B>Background</B></P><P>An improved risk stratification strategy beyond the measurement of conventional risk factors is needed to identify women at high risk of CAD.</P><P><B>Methods</B></P><P>The BBC (Women Health Registry Study for Bone, Breast, and Coronary Artery Disease) enrolled 2,100 asymptomatic women who underwent dual-energy X-ray absorptiometry, digital mammography, and coronary computed tomography angiography. We assessed the predicted 10-year atherosclerotic cardiovascular disease (ASCVD) risk and evaluated the presence and severity of BAC, LBM, coronary artery calcification (CAC), and coronary atherosclerotic plaque (CAP).</P><P><B>Results</B></P><P>CAC and CAP were found in 11.2% and 15.6% of participants, respectively. In women with CAC or CAP, increasing trends in the presence and severity of both BAC and LBM were observed. Both BAC and LBM were found to be associated with the presence of CAC (unadjusted odds ratios [OR]: 3.54 and 2.22, respectively) and CAP (unadjusted OR: 3.02 and 1.91, respectively). However, in multivariate analysis, only the presence of BAC and BAC score remained as independent predictors. For the prediction of CAC and CAP, addition of the BAC presence to the 10-year ASCVD risk significantly increased the areas under the curve (area under the curve: 0.71 to 0.72; p = 0.016; and area under the curve: 0.66 to 0.68; p = 0.010; respectively) and resulted in net reclassification index improvements (area under the curve: 0.304; p <0.001; and area under the curve: 0.245; p <0.001; respectively).</P><P><B>Conclusions</B></P><P>The presence and severity of BAC and LBM were significantly associated with the risk of subclinical CAD in asymptomatic women. BAC evaluation especially provides an independent and incremental value over conventional risk algorithms. (Women Health Cohort for Breast, Bone and Coronary Artery Disease [BBC]; NCT03235622)</P>

Cancer-Associated Splicing Variant of Tumor Suppressor AIMP2/p38: Pathological Implication in Tumorigenesis

Choi, Jin Woo,Kim, Dae Gyu,Lee, Al-Eum,Kim, Hye Rim,Lee, Jin Young,Kwon, Nam Hoon,Shin, Young Kee,Hwang, Soon-Kyung,Chang, Seung-Hee,Cho, Myung-Haing,Choi, Yoon-La,Kim, Jhingook,Oh, Seung Hyun,Kim, Bo Public Library of Science 2011 PLoS genetics Vol.7 No.3

<P>Although ARS-interacting multifunctional protein 2 (AIMP2, also named as MSC p38) was first found as a component for a macromolecular tRNA synthetase complex, it was recently discovered to dissociate from the complex and work as a potent tumor suppressor. Upon DNA damage, AIMP2 promotes apoptosis through the protective interaction with p53. However, it was not demonstrated whether AIMP2 was indeed pathologically linked to human cancer. In this work, we found that a splicing variant of AIMP2 lacking exon 2 (AIMP2-DX2) is highly expressed by alternative splicing in human lung cancer cells and patient's tissues. AIMP2-DX2 compromised pro-apoptotic activity of normal AIMP2 through the competitive binding to p53. The cells with higher level of AIMP2-DX2 showed higher propensity to form anchorage-independent colonies and increased resistance to cell death. Mice constitutively expressing this variant showed increased susceptibility to carcinogen-induced lung tumorigenesis. The expression ratio of AIMP2-DX2 to normal AIMP2 was increased according to lung cancer stage and showed a positive correlation with the survival of patients. Thus, this work identified an oncogenic splicing variant of a tumor suppressor, AIMP2/p38, and suggests its potential for anti-cancer target.</P><P><B>Author Summary</B></P> <P>Lung cancer is one of the most common cancers and a leading cause of death resulting from cancer. Despite intensive investigation, effective therapeutic targets and reliable biomarkers are still limited. Here we found that a tumor suppressor, AIMP2 (MSC p38), produces a variant lacking a part of its structure in cancer tissues. We designated it AIMP2-DX2. This smaller version of AIMP2 compromises the normal tumor suppressive activity of AIMP2 and induces tumor formation. We also found that the expression of AIMP2-DX2 was increased according to cancer progression. In addition, the patients with higher expression of AIMP2-DX2 showed lower survival than those with lower levels of this variant. Suppression of AIMP2-DX2 slowed tumor growth, suggesting it as a new therapeutic target. In summary, this work newly identified a tumor-inducing factor, AIMP2-DX2, that can be used as a therapeutic target and biomarker associated with lung cancer.</P>

Gastrokine 1 regulates NF‐κB signaling pathway and cytokine expression in gastric cancers

Yoon, Jung Hwan,La Cho, Mi,Choi, Yoo Jin,Back, Ji Yeon,Park, Mi Kyung,Lee, Suk Woo,Choi, Byung Joon,Ashktorab, Hassan,Smoot, Duane T.,Nam, Suk Woo,Lee, Jung Young,Park, Won Sang Wiley Subscription Services, Inc., A Wiley Company 2013 Journal of cellular biochemistry Vol.114 No.8

<P><B>Abstract</B></P><P>Gastrokine 1 (GKN1) plays an important role in the gastric mucosal defense mechanism and also acts as a functional gastric tumor suppressor. In this study, we examined the effect of GKN1 on the expression of inflammatory mediators, including NF‐κB, COX‐2, and cytokines in <I>GKN1</I>‐transfected AGS cells and sh<I>GKN1</I>‐transfected HFE‐145 cells. Lymphocyte migration and cell viability were also analyzed after treatment with GKN1 and inflammatory cytokines in AGS cells by transwell chemotaxis and an MTT assay, respectively. In <I>GKN1</I>‐transfected AGS cells, we observed inactivation and reduced expression of NF‐κB and COX‐2, whereas sh<I>GKN1</I>‐transfected HFE‐145 cells showed activation and increased expression of NF‐κB and COX‐2. GKN1 expression induced production of inflammatory cytokines including IL‐8 and ‐17A, but decreased expression of IL‐6 and ‐10. We also found IL‐17A expression in 9 (13.6%) out of 166 gastric cancer tissues and its expression was closely associated with GKN1 expression. GKN1 also acted as a chemoattractant for the migration of Jurkat T cells and peripheral B lymphocytes in the transwell assay. In addition, GKN1 significantly reduced cell viability in both AGS and HFE‐145 cells. These data suggest that the GKN1 gene may inhibit progression of gastric epithelial cells to cancer cells by regulating NF‐κB signaling pathway and cytokine expression. J. Cell. Biochem. 114: 1800–1809, 2013. © 2013 Wiley Periodicals, Inc.</P>