E‐cadherin expression increases cell proliferation by regulating energy metabolism through nuclear factor‐κB in AGS cells

Park, Song Yi,Shin, Jee&#x2010,Hye,Kee, Sun&#x2010,Ho John Wiley and Sons Inc. 2017 Cancer Science Vol.108 No.9

<P>β‐Catenin is a central player in Wnt signaling, and activation of Wnt signaling is associated with cancer development. E‐cadherin in complex with β‐catenin mediates cell–cell adhesion, which suppresses β‐catenin‐dependent Wnt signaling. Recently, a tumor‐suppressive role for E‐cadherin has been reconsidered, as re‐expression of E‐cadherin was reported to enhance the metastatic potential of malignant tumors. To explore the role of E‐cadherin, we established an E‐cadherin‐expressing cell line, EC96, from AGS cells that featured undetectable E‐cadherin expression and a high level of Wnt signaling. In EC96 cells, E‐cadherin re‐expression enhanced cell proliferation, although Wnt signaling activity was reduced. Subsequent analysis revealed that nuclear factor‐κB (NF‐κB) activation and consequent c‐myc expression might be involved in E‐cadherin expression‐mediated cell proliferation. To facilitate rapid proliferation, EC96 cells enhance glucose uptake and produce ATP using both mitochondria oxidative phosphorylation and glycolysis, whereas AGS cells use these mechanisms less efficiently. These events appeared to be mediated by NF‐κB activation. Therefore, E‐cadherin re‐expression and subsequent induction of NF‐κB signaling likely enhance energy production and cell proliferation.</P>

<i>Thymus vulgaris</i> alleviates UVB irradiation induced skin damage <i>via</i> inhibition of MAPK / AP ‐1 and activation of Nrf2‐ ARE antioxidant system

Sun, Zhengwang,Park, Sang Yong,Hwang, Eunson,Zhang, Mengyang,Seo, Seul A.,Lin, Pei,Yi, Tae&#x2010,Hoo John Wiley and Sons Inc. 2017 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.21 No.2

<P><B>Abstract</B></P><P>Solar ultraviolet (UV) radiation‐induced reactive oxidative species is mainly responsible for the development of photoageing. Rosmarinic acid was one of the main bioactive components detected in <I>Thymus vulgaris</I> (TV) we extracted. In this study, UVB‐induced skin damages have been shown to be ameliorated by treatment with TV in hairless mice (HR‐1) skin, demonstrated by decreased matrix metalloproteinases (MMPs) and increased collagen production. However, the underlying molecular mechanism on which TV acted was unclear. We examined the photoprotective effects of TV against UVB and elucidated the molecular mechanism in normal human dermal fibroblasts. <I>Thymus vulgaris</I> remarkably prevented the UVB‐induced reactive oxygen species and lactate dehydrogenase. Dose‐dependent increase in glutathione, NAD(P)H: quinone oxidoreductase1 and heme oxygenase‐1, by TV was confirmed by increased nuclear accumulation of Nrf2. Furthermore, 5‐Methoxyindole‐2‐carboxylic acid was introduced as a specific inhibitor of dihydrolipoyl dehydrogenase (DLD). We demonstrated that Nrf2 expression was regulated by DLD, which was a tricarboxylic acid cycle‐associated protein that decreased after UVB exposure. Besides, TV significantly diminished UVB induced phosphorylation of mitogen activated protein kinases pathway, containing extracellular signal‐regulated kinase, Jun N‐terminal kinase and p38, which consequently reduced phosphorylated c‐fos and c‐jun. Our results suggest that TV is a potential botanical agent for use against UV radiation‐induced oxidative stress mediated skin damages.</P>

Loss of RUNX3 expression promotes cancer‐associated bone destruction by regulating CCL5 , CCL19 and CXCL11 in non‐small cell lung cancer

Kim, Hyun&#x2010,Jeong,Park, Junhee,Lee, Sun Kyoung,Kim, Ki Rim,Park, Kwang&#x2010,Kyun,Chung, Won&#x2010,Yoon John WileySons, Ltd 2015 The Journal of pathology Vol.237 No.4

<P><B>Abstract</B></P><P>Non‐small cell lung cancer (NSCLC) frequently metastasizes to bone, which is associated with significant morbidity and a dismal prognosis. RUNX3 functions as a tumour suppressor in lung cancer and loss of expression occurs more frequently in invasive lung adenocarcinoma than in pre‐invasive lesions. Here, we show that RUNX3 and RUNX3‐regulated chemokines are linked to NSCLC‐mediated bone resorption. Notably, the receptor activator of nuclear factor‐κB ligand (RANKL)/osteoprotegerin (OPG) ratio, an index of osteoclastogenic stimulation, was significantly increased in human osteoblastic cells treated with conditioned media derived from RUNX3‐knockdown NSCLC cells. We aimed to identify RUNX3‐regulated factors that modify the osteoblastic RANKL/OPG ratio and found that RUNX3 knockdown led to CCL5 up‐regulation and down‐regulation of CCL19 and CXCL11 in NSCLC cells. Tumour size was noticeably increased and more severe osteolytic lesions were induced in the calvaria and tibiae of mice that received RUNX3‐knockdown cells. In response to RUNX3 knockdown, serum and tissue levels of CCL5 increased, whereas CCL19 and CXCL11 decreased. Furthermore, CCL5 increased the proliferation, migration, and invasion of lung cancer cells in a dose‐dependent manner; however, CCL19 and CXCL11 did not show any significant effects. The RANKL/OPG ratio in osteoblastic cells was increased by CCL5 but reduced by CCL19 and CXCL11. CCL5 promoted osteoclast differentiation, but CCL19 and CXCL11 reduced osteoclastogenesis in RANKL‐treated bone marrow macrophages. These findings suggest that RUNX3 and related chemokines are useful markers for the prediction and/or treatment of NSCLC‐induced bone destruction. © 2015 The Authors. <I>The Journal of Pathology</I> published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.</P>

Downregulation of CHIP promotes ovarian cancer metastasis by inducing Snail‐mediated epithelial–mesenchymal transition

Park, Sun&#x2010,Mi,Park, Seung&#x2010,Ho,Ryu, Ki&#x2010,Jun,Kim, In&#x2010,Kyu,Han, Hyeontak,Kim, Hyo&#x2010,Jin,Kim, Seon&#x2010,Hee,Hong, Keun&#x2010,Seok,Kim, Hyemin,Kim, Minju,Cho, Bok Im,Heo, Je Elsevier Science B.V. Amsterdam 2019 MOLECULAR ONCOLOGY Vol.13 No.5

<P>The epithelial–mesenchymal transition (EMT) plays a pivotal role in the conversion of early‐stage tumors into invasive malignancies. The transcription factor Snail, an extremely unstable protein whose subcellular levels are regulated by many E3 ubiquitin ligases, promotes EMT as well as associated pathological characteristics including migration, invasion, and metastasis. Through yeast two‐hybrid screening, we identified the carboxyl terminus of Hsc70‐interacting protein (CHIP) as a novel Snail ubiquitin ligase that interacts with Snail to induce ubiquitin‐mediated proteasomal degradation. Inhibition of CHIP expression increases Snail protein levels, induces EMT, and enhances <I>in vitro</I> migration and invasion as well as <I>in vivo</I> metastasis of ovarian cancer cells. In turn, Snail depletion abrogates all phenomena induced by CHIP depletion. Finally, Snail and CHIP expression is inversely correlated in ovarian tumor tissues. These findings establish the CHIP–Snail axis as a post‐translational mechanism of EMT and cancer metastasis regulation.</P>

Tolerability, effectiveness and predictive parameters for the therapeutic usefulness of exenatide in obese, K orean patients with type 2 diabetes

Song, Sun Ok,Kim, Kwang Joon,Lee, Byung&#x2010,Wan,Kang, Eun Seok,Cha, Bong Soo,Lee, Hyun Chul Wiley-Blackwell 2014 Journal of diabetes investigation Vol.5 No.5

<P><B>Abstract</B></P><P><B>Aims/Introduction</B></P><P>We assessed the tolerability, effectiveness and predictive parameters for the therapeutic usefulness of exenatide in obese Korean participants with type 2 diabetes. We also evaluated the characteristics of participants who respond adequately to glucagon‐like peptide‐1 (GLP‐1) analog therapy in terms of glycated hemoglobin (HbA1c) level reductions and weight loss.</P><P><B>Materials and Methods</B></P><P>This prospective, observational, single‐arm (exenatide b.i.d. in combination with both metformin and sulphonylurea), open‐label study of GLP‐1 analog treatment with close monitoring of metabolic parameters and weight changes was carried out for up to 22 weeks.</P><P><B>Results</B></P><P>Of the 110 enrolled obese participants, 37 participants dropped out during the 22‐week treatment period. A total of 73 participants completed the study (median age 55.0 years, interquartile range 44.0–65.0). The median duration of diabetes was 8.0 years (interquartile range 3.5–12.5) with a mean HbA1c value of 7.6% (interquartile range 7.00–8.55). The median body mass index was 30.78 kg/m<SUP>2</SUP> (interquartile range 27.89–33.92). After 22 weeks, median changes from baseline for HbA1c levels and weight were −0.7% and −3.0 kg, respectively, which were significant. No severe hypoglycemic events were observed. Multivariate regression analysis showed that C‐peptide values were a significant independent predictor for a reduction in HbA1c levels (β = 0.865, <I>P</I> = 0.018) with exenatide BID in combination with both sulphonylurea and metformin in obese Korean participants with type 2 diabetes and insulin naïveté.</P><P><B>Conclusions</B></P><P>Clinical and laboratory parameters, such as insulin naïveté and preserved β‐cell function, should be taken into consideration as important factors in the choice of GLP‐1 analog when predicting GLP‐1 analog responsiveness. This trial was registered with the local committee at Yonsei University in Korea (4‐2011‐0032).</P>

Increased miR‐223 expression in foetal organs is a signature of acute chorioamnionitis with systemic consequences

Lee, JoonHo,Kim, Chong Jai,Kim, Jung&#x2010,Sun,Lee, Deug&#x2010,Chan,Ahn, Sejin,Yoon, Bo Hyun John Wiley and Sons Inc. 2018 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.22 No.2

<P><B>Abstract</B></P><P>Acute chorioamnionitis, frequently observed in preterm placentas, is a major risk factor for the development of infection and non‐infection‐related adverse perinatal outcomes. MicroRNAs play important roles in immune cell development and function as well as in the development of cancers and neurologic diseases. We sought to investigate the changes in microRNA‐223 (miR‐223) expression and the functional significance of the changes in miR‐223 expression in foetal organs in the presence of acute chorioamnionitis. Using formalin‐fixed, paraffin‐embedded (FFPE) tissue samples from foetal or neonatal autopsy cases, which are the most practical option to study the changes in several organs simultaneously, miR‐223 expression profiles in foetal thymus, lung and liver were compared between cases with and without acute chorioamnionitis. Total RNA was extracted from FFPE specimens and qRT‐PCR was conducted. miR‐223‐3p expression levels in foetal thymus (2.55‐fold), lung (1.93‐fold) and liver (1.70‐fold) were significantly higher in cases with acute chorioamnionitis than in those without. Transfection of pre‐miR‐223‐3p in Jurkat cells and luciferase assay and ribonucleoprotein immunoprecipitation followed by qRT‐PCR analysis confirmed the binding of miR‐223 to the 3′ untranslated region (3′UTR) of forkhead box O1 (FoxO1) mRNA and the regulation of FoxO1 by miR‐223. We report for the first time that foetuses with inflammation in the chorioamniotic membranes show increased expression of miR‐223 in the thymus, lung and liver. Furthermore, FoxO1 is a target of miR‐223. These findings suggest that post‐transcriptional regulation of genes by miR‐223 is a component of the foetal inflammatory response, which has systemic consequences in the foetus.</P>

Safety and efficacy of single‐agent docetaxel ( T axotere) administered weekly in non‐small cell lung carcinoma patients in K orea: An observational study

Lim, Sun Min,Park, Byeong Bae,Park, Keun&#x2010,Chil,Kim, Hoon&#x2010,Kyo,Lee, Jong Seok,Bae, Sung Hwa,Lee, Seung&#x2010,Sei,Kang, Jin&#x2010,Hyoung,Park, Se&#x2010,Hoon,Lee, Gyeong&#x2010,Won,Lee, Hy John Wiley and Sons Inc. 2016 Thoracic cancer Vol.7 No.2

<P><B>Abstract</B></P><P><B>Background</B></P><P>To investigate the efficacy, safety, and tolerability of weekly docetaxel treatment in advanced non‐small cell lung cancer (NSCLC) patients in Korea.</P><P><B>Methods</B></P><P>This prospective observational study included Korean advanced NSCLC patients with Eastern Cooperative Oncology Group performance status <2 who received weekly monotherapy of docetaxel at a dose determined by the physician. Efficacy measurements included tumor response rate, overall survival (OS), progression‐free survival, and one‐year survival rate. Safety was analyzed through recorded incidences of adverse events (AEs), serious adverse events (SAEs), deaths, and other related safety parameters, along with their toxicity grades.</P><P><B>Results: </B></P><P>Of 274 patients analyzed, one patient achieved a complete response and 42 partial responses; thus, the overall response rate was 15.7%. The OS rate at baseline and at one‐year follow‐up was 38.3% and 33.8%, respectively. AEs were reported in 229 (83.6%) patients. The most frequently reported hematologic AE of grade ≥3 was a decrease in neutrophils, with 6.6% of the patients developing neutropenia. In non‐hematologic AEs of grade ≥3, the most common were infection with unknown absolute neutrophil count and death not associated with Common Terminology Criteria for Adverse Events (CTCAE) (4.7% each). The most common SAE reported was death, not associated with CTCAE (7.3%).</P><P><B>Conclusions</B></P><P>In Korean patients, the weekly regimen of docetaxel monotherapy was safe and efficacious against advanced NSCLC.</P>

NEDD 4‐induced degradative ubiquitination of phosphatidylinositol 4‐phosphate 5‐kinase α and its implication in breast cancer cell proliferation

Tran, Mai Hoang,Seo, Eunjeong,Min, Soohong,Nguyen, Quynh&#x2010,Anh T.,Choi, Juyong,Lee, Uk&#x2010,Jin,Hong, Soon&#x2010,Sun,Kang, Hyuk,Mansukhani, Alka,Jou, Ilo,Lee, Sang Yoon John Wiley and Sons Inc. 2018 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.22 No.9

<P><B>Abstract</B></P><P>Phosphatidylinositol 4‐phosphate 5‐kinase (PIP5K) family members generate phosphatidylinositol 4,5‐bisphosphate (PIP2), a critical lipid regulator of diverse physiological processes. The PIP5K‐dependent PIP2 generation can also act upstream of the oncogenic phosphatidylinositol 3‐kinase (PI3K)/Akt pathway. Many studies have demonstrated various mechanisms of spatiotemporal regulation of PIP5K catalytic activity. However, there are few studies on regulation of PIP5K protein stability. Here, we examined potential regulation of PIP5Kα, a PIP5K isoform, via ubiquitin‐proteasome system, and its implication for breast cancer. Our results showed that the ubiquitin ligase NEDD4 (neural precursor cell expressed, developmentally down‐regulated gene 4) mediated ubiquitination and proteasomal degradation of PIP5Kα, consequently reducing plasma membrane PIP2 level. NEDD4 interacted with the C‐terminal region and ubiquitinated the N‐terminal lysine 88 in PIP5Kα. In addition, PIP5Kα gene disruption inhibited epidermal growth factor (EGF)‐induced Akt activation and caused significant proliferation defect in breast cancer cells. Notably, PIP5Kα K88R mutant that was resistant to NEDD4‐mediated ubiquitination and degradation showed more potentiating effects on Akt activation by EGF and cell proliferation than wild‐type PIP5Kα. Collectively, these results suggest that PIP5Kα is a novel degradative substrate of NEDD4 and that the PIP5Kα‐dependent PIP2 pool contributing to breast cancer cell proliferation through PI3K/Akt activation is negatively controlled by NEDD4.</P>

Incidence, predictors, and outcomes of distal vessel expansion on follow‐up intravascular ultrasound after recanalization of chronic total occlusions using new‐generation drug‐eluting stents: Data from the CTO‐IVUS randomized

Hong, Sung&#x2010,Jin,Kim, Byeong&#x2010,Keuk,Kim, Young&#x2010,Joo,Rha, Seung&#x2010,Woon,Lee, Seung&#x2010,Jin,Kim, Hee&#x2010,Yeol,Choi, Jin&#x2010,Ho,Ahn, Chul&#x2010,Min,Kim, Jung&#x2010,Sun,Ko, John WileySons, Inc. 2020 Catheterization and cardiovascular interventions Vol.95 No.1

<P><B>Abstract</B></P><P><B>Objectives</B></P><P>To evaluate the incidence, predictors, and outcomes of distal vessel expansion on intravascular ultrasound (IVUS) after recanalization of chronic total occlusion (CTO) particularly using new‐generation drug‐eluting stent (DES).</P><P><B>Background</B></P><P>The luminal changes of narrowed vessels distal to CTO segments after recanalization using new‐generation DES have rarely been studied.</P><P><B>Methods</B></P><P>This substudy of the CTO‐IVUS (Chronic Total Occlusion InterVention with drUg‐eluting Stents) trial included a total of 69 new‐generation DES‐treated CTOs with serial matched IVUS analyses at index percutaneous coronary intervention (PCI) and at 1‐year follow‐up. The predictors of distal vessel expansion, any increase of lumen area at the distal reference (LA<SUB>distal</SUB>) on 1‐year follow‐up IVUS, were evaluated by multivariable binary logistic analyses.</P><P><B>Results</B></P><P>Distal vessel expansion was identified in 46 (67%). Independent determinants of distal vessel expansion were proximal CTO, a smaller LA<SUB>distal</SUB> at the index PCI, a greater minimal stent area‐to‐LA<SUB>distal</SUB> (MSA‐to‐LA<SUB>distal</SUB>) ratio, and a greater lumen area at the distal stent edge‐to‐LA<SUB>distal</SUB> (LA<SUB>edge</SUB>‐to‐LA<SUB>distal</SUB>) ratio. The cut‐off values of a MSA‐to‐LA<SUB>distal</SUB> ratio and a LA<SUB>edge</SUB>‐to‐LA<SUB>distal</SUB> ratio predicting the distal vessel expansion by receiver operating characteristic curve analysis were 1.0 and 1.1, respectively. During the median 5.1 years, rates of target vessel revascularization, cardiac death, and stent thrombosis were similar in the distal vessel‐expanded and nonexpanded groups.</P><P><B>Conclusion</B></P><P>After opening CTO with new‐generation DES, two‐thirds of patients exhibited distal vessel expansion on 1‐year follow‐up IVUS. Expansion determinants were a proximal CTO, lower LA<SUB>distal</SUB>, and larger stent areas relative to the LA<SUB>distal</SUB> (modifiable procedural predictors).</P>

Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate‐induced colitis in mice due to increased intestinal permeability

Kim, Ye&#x2010,Ryung,Volpert, Giora,Shin, Kyong&#x2010,Oh,Kim, So&#x2010,Yeon,Shin, Sun&#x2010,Hye,Lee, Younghay,Sung, Sun Hee,Lee, Yong&#x2010,Moon,Ahn, Jung&#x2010,Hyuck,Pewzner&#x2010,Jung, Yael,Pa John Wiley and Sons Inc. 2017 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.21 No.12

<P><B>Abstract</B></P><P>Ceramides mediate crucial cellular processes including cell death and inflammation and have recently been implicated in inflammatory bowel disease. Ceramides consist of a sphingoid long‐chain base to which fatty acids of various length can be attached. We now investigate the effect of alerting the ceramide acyl chain length on a mouse model of colitis. Ceramide synthase (CerS) 2 null mice, which lack very‐long acyl chain ceramides with concomitant increase of long chain bases and C16‐ceramides, were more susceptible to dextran sodium sulphate‐induced colitis, and their survival rate was markedly decreased compared with that of wild‐type littermates. Using mixed bone‐marrow chimeric mice, we showed that the host environment is primarily responsible for intestinal barrier dysfunction and increased intestinal permeability. In the colon of CerS2 null mice, the expression of junctional adhesion molecule‐A was markedly decreased and the phosphorylation of myosin light chain 2 was increased. <I>In vitro</I> experiments using Caco‐2 cells also confirmed an important role of CerS2 in maintaining epithelial barrier function; CerS2‐knockdown <I>via </I>CRISPR‐Cas9 technology impaired barrier function. <I>In vivo</I> myriocin administration, which normalized long‐chain bases and C16‐ceramides of the colon of CerS2 null mice, increased intestinal permeability as measured by serum FITC‐dextran levels, indicating that altered SLs including deficiency of very‐long‐chain ceramides are critical for epithelial barrier function. In conclusion, deficiency of CerS2 influences intestinal barrier function and the severity of experimental colitis and may represent a potential mechanism for inflammatory bowel disease pathogenesis.</P>