Clinicopathological Implication of Insulin-like Growth Factor-II mRNA-Binding Protein 3 (IMP3) Expression in Gastric Cancer

LEE, DAKEUN,YU, EUN JI,HAM, IN-HYE,HUR2, HOON Potamitis Press 2017 Anticancer research Vol.37 No.1

<P>Background: The clinicopathological significance of oncofetal mRNA-binding protein, human insulin-like growth factor II mRNA-binding protein 3 (IMP3), in gastric carcinoma (GC) is not fully understood. Materials and Methods: Tissue microarray blocks with specimens from 346 patients with GC were constructed to evaluate the clinicopathological role of IMP3 expression in GC. These results were validated with an online dataset of 876 patients from the Kaplan-Meier Plotter. Sera from 15 controls and 57 patients with GC were collected in order to compare the levels of serum IMP3 between groups. Results: High expression of IMP3 was significantly associated with poor prognosis. Survival curves from the Kaplan-Meier Plotter showed that high IMP3 expression was significantly related to worse disease-free survival and overall survival. Conclusion: Tissue overexpression of IMP3 might be used as a predictor of advanced disease or lymph node metastasis, and is associated with poorer prognosis in GCs.</P>

Neural Invasion is a Significant Contributor to Peritoneal Recurrence in Signet Ring Cell Gastric Carcinoma

Lee, Dakeun,Son, Sang-Yong,Kim, Young-Bae,Han, Sang-Uk,Hur, Hoon Springer - Society of Surgical Oncology 2018 Annals of Surgical Oncology Vol.25 No.5

S-54 : Primary Gastric Histiocytic sarcoma, similar with an inflammatory pseudotumor: A Case report

( Choong Kyun Noh ),( Sook Hee Chung ),( Dakeun Lee ),( Sung Jae Shin ),( Joon Koo Kang ),( Sun Kyo Lim ),( Kee Myung Lee ),( Kyang Jae Lee ) 대한내과학회 2013 대한내과학회 추계학술대회 Vol.2013 No.1

Histiocytic sarcoma is a malignant neoplasm that originated from myeloid-derived macrophages, and related to myelomonocytic or lymphoblastic leukemia. Histiocytic sarcoma rarely occurs in the stomach. In previous reports, a few cases of histiocytic sarcoma in the stomach were reported. In this case, a 45-year-old female had complained of patient epigastric pain and melena for 1 month. In her laboratory data, hemoglobin was 8 g/dl. In endoscopic finding, there was an ulcerofungating mass with irregular base coated with dirty exudates in distal antrum and body. Abdominal Computed tomography showed a large ulcerofungating mass involving from gastric antrum to duodenal bulb with suspicious invasion of pancreas. In PET CT, metastatic lymph nodes in infrapyloric, perigastric and right hilar area were found. In pathologic findings, tumor cells showed band-like infiltration mainly in the mucosa and submucosa, but also penetrated into serosa in some areas. Tumor cells largely had intermediate-size nuclei with plump, pink cytoplasm. Because there was lack of high degree of cellular atypia or pleomorphism in pathologic findings, final diagnosis as gastric Histiocytic sarcoma was confused with inflammatory pseudotumor. In immunohistochemical staining, the tumor cells were positive for CD68, CD163, LCA, lysozyme, but negative for other immunomarkers including CD21, CD1a, and MPO. The patient underwent palliative distal gastrectomy. The resected specimen after operation clearly demonstrated the malignant nature of this tumor. Based upon the examination, the authors finally diagnosed her as histiocytic sarcoma. The patient was referred to oncology department after operation. She received chemotherapy such as Etoposide, Cisplatin and Iphosphamide. She has another schedules for additional chemotherapy in the out-patient department clinics.

Amplification of transglutaminase 2 enhances tumor-promoting inflammation in gastric cancers

Cho Sung-Yup,오유미,Jeong Eui Man,박상희,Dakeun Lee,Xiaorui Wang,Qiqi Zeng,Hongyu Qin,Fang Hu,Hui Gong,Xi Liu,Guanjun Zhang,나득채,이지은,채지수,서윤석,공성호,Hyuk-Joon Lee,Jong-Il Kim,박한수,Chengsheng Zhang,양한광,Charles Lee 생화학분자생물학회 2020 Experimental and molecular medicine Vol.52 No.-

Tumor-promoting inflammation is a hallmark of cancer and is highly associated with tumor progression, angiogenesis, and metastasis. Tumor-associated macrophages (TAMs) are major drivers of tumor-promoting inflammation, but due to the complexity of the tumor microenvironment, the detailed regulatory mechanisms are still under investigation. Here, we investigated a novel role for transglutaminase 2 (TGM2) in the development of tumor-promoting inflammation and recruitment of TAMs to gastric cancer (GC) tissues. When estimated by array comparative genomic hybridization and droplet digital PCR, the copy numbers of the TGM2 gene were amplified in 13.6% (14/103) of GC patients and positively associated with TGM2 expression. Gene set enrichment analysis of expression microarray data for GC samples with high or low TGM2 expression showed that increased TGM2 expression was associated with tumor-promoting inflammation in GC. In addition, the expression of TGM2 was correlated with the expression of markers for macrophages, neutrophils, blood vessels, and lymphatic vessels. Overexpression of TGM2 in GC cells augmented the IL-1β-induced secretion of macrophage-recruiting chemokines and NF-κB activation. TGM2 protein levels were associated with the expression levels of the macrophage marker CD163 in human GC tissue samples. Moreover, GC patients with high expression of TGM2 had a worse prognosis than those with low expression of TGM2. These results suggest TGM2 as a novel regulator of the tumor microenvironment of GC and provide a promising target for constraining tumor-promoting inflammation.

MicroRNA Expression Signatures Associated With <i>BRAF</i> -Mutated Versus <i>KRAS</i> -Mutated Colorectal Cancers

Choi, Yong Won,Song, Young Soo,Lee, Hyunwoo,Yi, Kijong,Kim, Young-Bae,Suh, Kwang Wook,Lee, Dakeun Williams & Wilkins Co 2016 Medicine Vol.95 No.15

<P><B>Abstract</B></P><P><I>BRAF</I> and <I>KRAS</I> genes are known to play a similar role in the activation of <I>RAS-RAF-MEK-ERK</I> signaling pathway in colorectal tumorigenesis. However, <I>BRAF</I>-mutated colorectal cancers (CRCs) have distinct clinicopathologic characteristics different from those of the <I>KRAS</I> mutated ones as in comparison the <I>BRAF</I>-mutated CRCs are associated with a much worse prognosis for the afflicted patients. This study aimed to determine the different miRNA expression signatures associated with <I>BRAF</I>-mutated CRCs in comparison to <I>KRAS</I>-mutated ones, and to identify the specific miRNAs possibly mediating the aggressive phenotype of the <I>BRAF</I>-mutated CRCs.</P><P>We screened 535 formalin-fixed paraffin-embedded CRC tissue samples for the <I>BRAF V600E</I> mutation, and selected 7 <I>BRAF</I>-mutated and 7 <I>KRAS</I>-mutated CRCs that were tumor size, stage, and microsatellite status-matched. Affymetrix GeneChip® miRNA 4.0 Array was used for detection of miRNA expression differences in the selected samples. We validated the array results by quantitative reverse transcription polymerase chain reaction (qRT-PCR) for selected miRNAs.</P><P>A total of 10 differentially expressed (DE) miRNAs associated with <I>BRAF</I>-mutated CRCs were obtained, including miR-31-5p, miR-877-5p, miR-362-5p, and miR-425-3p. miR-31-5p showed the highest fold change (8.3-fold) among all of the miRNAs analyzed. From the analyses of GO biological processes, the DE-miRNAs were functionally relevant to cellular proliferation such as positive regulation of gene expression (<I>P</I> = 1.26 × 10<SUP>−10</SUP>), transcription (<I>P</I> = 9.70 × 10<SUP>−10</SUP>), and RNA metabolic process (<I>P</I> = 1.97 × 10<SUP>−9</SUP>). Bioinformatics analysis showed that the DE-miRNAs were significantly enriched in cancer-associated pathways including neutrophin signaling (<I>P</I> = 6.84 × 10<SUP>−5</SUP>), pathways in cancer (<I>P</I> = 0.0016), Wnt signaling (<I>P</I> = 0.0027), and MAPK signaling pathway (<I>P</I> = 0.0036).</P><P>Our results suggest that the DE-miRNAs in <I>BRAF</I>-mutated CRCs in comparison to <I>KRAS</I>-mutated CRCs are implicated in the aggressive phenotype of the <I>BRAF</I>-mutated CRCs. Further experimental validation is required to confirm these results.</P>

Frequent EBV positivity in conventional adenocarcinomas occurring simultaneously with EBV-associated gastric cancers

Kim, Young-Bae,Hur, Hoon,Lee, Dakeun Wolters Kluwer UK Ltd. 2016 Pathology Vol.48 No.6

Familial Glycogen Storage Disease Type IXa Diagnosed by Targeted Exome Sequencing

손영배,장주영,이다근,장자현,Sohn, Young Bae,Jang, Ju Young,Lee, Dakeun,Jang, Ja-Hyun The Korean Society of Inherited Metabolic Disease 2017 대한유전성대사질환학회지 Vol.17 No.3

당원병 IX형은 phosphorylase kinase 효소 결핍으로 분해되지 않은 당원이 간 또는 근육에 축적되는 유전성대사이상질환이다. 당원병 IXa형은 당원병 IX형 중 가장 흔한 형태로 PHKA2 유전자 변이로 발생한다. 당원병 IXa형의 임상증상은 간 비대, 간 효소 수치 상승, 성장 지연, 저혈당 등이 있다. 그러나, 이러한 임상 증상은 다른 타입의 당원병의 증상과 비슷하거나 겹쳐서 임상적으로는 구분하기가 어렵다. 저자들은 표적 엑솜 시퀀싱으로 진단된 가족성 당원병 IXa형 증례를 보고하고자 한다. 4세 남아가 간 비대와 간 효소 수치 상승을 주소로 내원하였다. 간 조직검사결과 간세포에 당원이 축적되어 있어 당원병을 의심하였으나 G6PC 유전자 검사는 음성이었다. 이에 당원병 타입을 감별진단 하기 위해 표적 엑솜시퀀싱을 시행하였으며, PHKA2 유전자에서 질환과의 연관성이 이미 보고된 바 있는 c.3632C>T (p.Thr121Met) 변이가 반접합체(hemizygote)로 발견되어 당원병 IXa로 진단하였다. 가족 유전자 검사를 통해 어머니가 이형접합체 보인자임을 확인하였으며, 남동생이 같은 변이를 가진 반접합체임을 확인하였다. 28개월 된 환자의 남동생 역시 신체 검진 상 간 비대가 있었으며, 혈액검사상 간 효소 수치가 상승되어 있어 같은 질환으로 확진하였다. 이환된 형제 모두 생 옥수수 전분 섭취와 복합 탄수화물을 섭취하도록 식이 조절을 하였으며 2년 추적관찰 동안 정상 성장 발달을 보이고 있다. 당원병과 같이 임상적으로 구분이 어려우며 유전학적으로 다양한 유전자 변이를 보이는 당원병과 같은 질환의 분자 유전학적 감별진단에 표적 엑솜 시퀀싱이 유용한 진단법이 될 수 있다. 신속하고 정확한 분자 유전학적 감별진단을 통해 환자와 보호자에게 질병의 적절한 치료법, 질병의 예후에 관한 정확한 정보를 제공할 수 있을 뿐 아니라, 적절한 유전상담을 제공할 수 있다. Glycogen storage disease type IX (GSD IX) is caused by deficiency of phosphorylase kinase which plays a role in breakdown of glycogen. Mutations in PHKA2 are the most common cause of GSD IX (GSD IXa). Clinical manifestations of GSD IXa include hepatomegaly, elevation of liver enzyme, growth retardation, fasting hypoglycemia, and fasting ketosis. However, the symptoms overlap with those of other types of GSDs. Here, we report Korean familial cases with GSD IXa whose diagnosis was confirmed by targeted exome sequencing. A 4-year old male patient was presented with hepatomegaly and persistently elevated liver enzyme. Liver biopsy revealed swollen hepatocyte filled with glycogen storage, suggesting GSDs. Targeted exome sequencing was performed for the differential molecular diagnosis of various types of GSDs. A hemizygous mutation in PHKA2 were detected by targeted exome sequencing and confirmed by Sanger sequencing: c.3632C>T (p.Thr121Met), which was previously reported. The familial genetic analysis revealed that his mother was heterozygous carrier of c.3632C>T mutation and his 28-month old brother had hemizygous mutation. His brother also had hepatomegaly and elevated liver enzyme. The hypoglycemia was prevented by frequent meals with complex carbohydrate, as well as cornstarch supplements. Their growth and development is in normal range. We suggest that targeted exome sequencing could be a useful diagnostic tool for the genetically heterogeneous and clinically indistinguishable GSDs. A precise molecular diagnosis of GSD can provide appropriate therapy and genetic counseling for the family.

Inhibition of Discoidin Domain Receptor 1 Prevents Stroma-Induced Peritoneal Metastasis in Gastric Carcinoma

Jin, Hyejin,Ham, In-Hye,Oh, Hye Jeong,Bae, Cheong A,Lee, Dakeun,Kim, Young-Bae,Son, Sang-Yong,Chwae, Yong-Joon,Han, Sang-Uk,Brekken, Rolf A.,Hur, Hoon American Association for Cancer Research 2018 Molecular Cancer Research Vol.16 No.10

<P>Discoidin domain receptor 1 (DDR1) is activated by fibrillar (triple-helical) collagens and collagen IV, which are major components of tumor stroma; thus, DDR1 might be a critical mediator of communication between cancer cells and stroma. The aim of this study was to investigate the effect of DDR1 inhibition on stroma-induced peritoneal metastasis in gastric carcinoma. We analyzed by immunohistochemistry the correlation between DDR1 expression and the pattern of recurrence in gastric carcinoma tissues from a previously characterized and established gastric carcinoma patient cohort. We also cocultured human gastric carcinoma cell lines with gastric cancer–associated fibroblasts (CAF) and investigated DDR1 expression and activation. We evaluated CAF-induced tumorigenic properties of gastric carcinoma cell lines and the effect of a DDR1-specific inhibitor in organotypic cultures and in a peritoneal seeding xenograft animal model. The expression of DDR1 in gastric cancer tissues was positively associated with early recurrence (<I>P</I> = 0.043) and a high incidence of peritoneal recurrence (<I>P</I> = 0.036). We confirmed that coculturing with CAFs elevated DDR1 protein expression in gastric carcinoma cell lines and enhanced gastric carcinoma cell line spheroid formation in organotypic cultures in a tumor cell DDR1-dependent manner. Coimplantation of CAFs with gastric carcinoma cells enhanced peritoneal tumor formation <I>in vivo</I>, an effect that was sensitive to pharmacologic inhibition of DDR1.</P><P><B>Implications:</B> This study highlights that CAF-induced elevation of DDR1 expression in gastric carcinoma cells enhances peritoneal tumorigenesis, and that inhibition of DDR1 is an attractive strategy for the treatment of gastric carcinoma peritoneal metastasis. <I>Mol Cancer Res; 16(10); 1590–600. ©2018 AACR</I>.</P>

Functional loss of ARID1A is tightly associated with high PD‐L1 expression in gastric cancer

Kim, Young‐,Bae,Ahn, Ji Mi,Bae, Won Jung,Sung, Chang Ohk,Lee, Dakeun John Wiley Sons, Inc. 2019 International journal of cancer: Journal internati Vol.145 No.4

<P>Notwithstanding remarkable treatment success with anti‐PD‐1 monoclonal antibody, oncogenic mechanism of PD‐L1 regulation in gastric cancer (GC) remains poorly understood. We hypothesized that ARID1A might be related to tumor PD‐L1 expression in GC. We found that tumor PD‐L1 positivity was associated with loss of ARID1A and showed trend toward better survival of patients with various molecular subtypes of GC (experimental set, n = 273). Considering heterogeneous ARID1A expression, we validated this using whole tissue sections (n = 159) and found that loss of ARID1A was correlated with microsatellite instability‐high (MSI‐H), Epstein–Barr virus (EBV), and PD‐L1 positivity. Furthermore, for patients with MSI‐H tumors, the degree of PD‐L1 expression was significantly higher in ARID1A‐deficient tumors. After ARID1A knockdown in GC cell lines, total and membranous PD‐L1 protein, and PD‐L1 mRNA levels were increased based on Western blot, flow cytometry, and qRT‐PCR, respectively. With IFN‐γ treatment, PD‐L1 expression was significantly increased both in ARID1A‐deficient cancer cells and controls, but the increase was not more pronounced in the former. Loss of ARID1A increased PD‐L1 <I>via</I> activating AKT signaling, while LY294002 (PI3K inhibitor) decreased PD‐L1 levels. Furthermore, we found that 3 MSI‐H tumors showing highest expression of PD‐L1 had simultaneous <I>KRAS</I> mutation and loss of ARID1A, suggesting a possible synergistic role boosting PD‐L1. Our results strongly indicate that loss of ARID1A is tightly associated with high PD‐L1 expression in GC. These results would increase our understanding of the oncogenic mechanism of PD‐L1 regulation in GC, and also help to find the optimal candidates for immunotherapy.</P>