A prognostic index based on an eleven gene signature to predict systemic recurrences in colorectal cancer

Seon-Kyu Kim,Seon-Young Kim,Chan Wook Kim,Seon Ae Roh,하예진,Jong Lyul Lee,Haejeong Heo,Dong-Hyung Cho,이주석,Yong Sung Kim,Jin Cheon Kim 생화학분자생물학회 2019 Experimental and molecular medicine Vol.51 No.-

Approximately half of colorectal cancer (CRC) patients experience disease recurrence and metastasis, and theseindividuals frequently fail to respond to treatment due to their clinical and biological diversity. Here, we aimed toidentify a prognostic signature consisting of a small gene group for precisely predicting CRC heterogeneity. Weperformed transcriptomic profiling using RNA-seq data generated from the primary tissue samples of 130 CRCpatients. A prognostic index (PI) based on recurrence-associated genes was developed and validated in two largerindependent CRC patient cohorts (n = 795). The association between the PI and prognosis of CRC patients wasevaluated using Kaplan–Meier plots, log-rank tests, a Cox regression analysis and a RT-PCR analysis. Transcriptomicprofiling in 130 CRC patients identified two distinct subtypes associated with systemic recurrence. Pathwayenrichment and RT-PCR analyses revealed an eleven gene signature incorporated into the PI system, which was asignificant prognostic indicator of CRC. Multivariate and subset analyses showed that PI was an independent risk factor(HR = 1.812, 95% CI = 1.342–2.448, P < 0.001) with predictive value to identify low-risk stage II patients who respondedthe worst to adjuvant chemotherapy. Finally, a comparative analysis with previously reported Consensus MolecularSubgroup (CMS), high-risk patients classified by the PI revealed a distinct molecular property similar to CMS4,associated with a poor prognosis. This novel PI predictor based on an eleven gene signature likely represents asurrogate diagnostic tool for identifying high-risk CRC patients and for predicting the worst responding patients foradjuvant chemotherapy.

Regional Differences of Proteins Expressing in Adipose Depots Isolated from Cows, Steers and Bulls as Identified by a Proteomic Approach

Cho, Jin Hyoung,Jeong, Jin Young,Lee, Ra Ham,Park, Mi Na,Kim, Seok-Ho,Park, Seon-Min,Shin, Jae-Cheon,Jeon, Young-Joo,Shim, Jung-Hyun,Choi, Nag-Jin,Seo, Kang Seok,Cho, Young Sik,Kim, MinSeok S.,Ko, Sun Asian Australasian Association of Animal Productio 2016 Animal Bioscience Vol.29 No.8

Adipose tissue in the loin muscle area of beef cattle as a marbling factor is directly associated with beef quality. To elucidate whether properties of proteins involved in depot specific adipose tissue were sex-dependent, we analyzed protein expression of intramuscular adipose tissue (IMAT) and omental adipose tissue (OMAT) from Hanwoo cows, steers, and bulls of Korean native beef cattle by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic analysis, quantitative polymerase chain reaction (PCR) and western blot analysis. Two different adipose depots (i.e. intramuscular and omental) were collected from cows (n = 7), steers (n = 7), or bulls (n = 7). LC-MS/MS revealed a total of 55 and 35 proteins in IMAT and OMAT, respectively. Of the 55 proteins identified, 44, 40, and 42 proteins were confirmed to be differentially expressed in IMAT of cows, steers, and bulls, respectively. In OMAT of cows, steers, and bulls, 33, 33, and 22 were confirmed to be differentially expressed, respectively. Tropomyosin (TPM) 1, TPM 2, and TPM3 were subjected to verification by quantitative PCR and western blot analysis in IMAT and OMAT of Hanwoo cows, steers, and bulls as key factors closely associated with muscle development. Both mRNA levels and protein levels of TPM1, TPM2, and TPM3 in IMAT were lower in bulls compared to in cows or steers suggesting that they were positively correlated with marbling score and quality grade. Our results may aid the regulation of marbling development and improvement of meat quality grades in beef cattle.

Gene expression profiling: canonical molecular changes and clinicopathological features in sporadic colorectal cancers.

Kim, Jin-Cheon,Kim, Seon-Young,Roh, Seon-Ae,Cho, Dong-Hyung,Kim, Dae-Dong,Kim, Jeong-Hyun,Kim, Yong-Sung WJG Press 2008 World journal of gastroenterology Vol.14 No.43

<P>To investigate alternative or subordinate pathways involved in colorectal tumorigenesis and tumor growth, possibly determining at-risk populations and predicting responses to treatment.</P>

Proteomic Assessment of the Relevant Factors Affecting Pork Meat Quality Associated with Longissimus dorsi Muscles in Duroc Pigs

Cho, Jin Hyoung,Lee, Ra Ham,Jeon, Young-Joo,Park, Seon-Min,Shin, Jae-Cheon,Kim, Seok-Ho,Jeong, Jin Young,Kang, Hyun-sung,Choi, Nag-Jin,Seo, Kang Seok,Cho, Young Sik,Kim, MinSeok S.,Ko, Sungho,Seo, Jae Asian Australasian Association of Animal Productio 2016 Animal Bioscience Vol.29 No.11

Meat quality is a complex trait influenced by many factors, including genetics, nutrition, feeding environment, animal handling, and their interactions. To elucidate relevant factors affecting pork quality associated with oxidative stress and muscle development, we analyzed protein expression in high quality longissimus dorsi muscles (HQLD) and low quality longissimus dorsi muscles (LQLD) from Duroc pigs by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic analysis. Between HQLD (n = 20) and LQLD (n = 20) Duroc pigs, 24 differentially expressed proteins were identified by LC-MS/MS. A total of 10 and 14 proteins were highly expressed in HQLD and LQLD, respectively. The 24 proteins have putative functions in the following seven categories: catalytic activity (31%), ATPase activity (19%), oxidoreductase activity (13%), cytoskeletal protein binding (13%), actin binding (12%), calcium ion binding (6%), and structural constituent of muscle (6%). Silver-stained image analysis revealed significant differential expression of lactate dehydrogenase A (LDHA) between HQLD and LQLD Duroc pigs. LDHA was subjected to in vitro study of myogenesis under oxidative stress conditions and LDH activity assay to verification its role in oxidative stress. No significant difference of mRNA expression level of LDHA was found between normal and oxidative stress condition. However, LDH activity was significantly higher under oxidative stress condition than at normal condition using in vitro model of myogenesis. The highly expressed LDHA was positively correlated with LQLD. Moreover, LDHA activity increased by oxidative stress was reduced by antioxidant resveratrol. This paper emphasizes the importance of differential expression patterns of proteins and their interaction for the development of meat quality traits. Our proteome data provides valuable information on important factors which might aid in the regulation of muscle development and the improvement of meat quality in longissimus dorsi muscles of Duroc pigs under oxidative stress conditions.

Growth and Invasion of Sporadic Colorectal Adenocarcinomas in Terms of Genetic Change

Roh, Seon Ae,Choi, Eun Young,Cho, Dong Hyung,Jang, Se Jin,Kim, Seon Young,Kim, Yong Sung,Kim, Jin Cheon The Korean Academy of Medical Sciences 2010 JOURNAL OF KOREAN MEDICAL SCIENCE Vol.25 No.3

<P>Integrative genetic changes were examined in relation to tumor growth and progression of sporadic colorectal cancers. Ninety-two sporadic colorectal cancer patients and 12 human colorectal cancer cell lines were evaluated. Genetic changes in representative steps of colorectal tumorigenesis were determined. Biological characteristics, i.e., clinicopathologic parameters, expression of invasion-associated molecules, and in vitro invasion and migration, in association with these changes were further analyzed. Adenomatous polyposis coli (APC) and/or Wnt-activated alterations occurred in 66% patients, whereas mismatch repair (MMR) defects and/or RAF-mediated alterations were identified in 47% patients. The crossover rate between these two alterations was 26%. Differential mRNA expression of <I>ARK5</I> was closely associated with that of <I>MMP2</I>, <I>MMP9</I>, and <I>S100A4</I> (<I>P</I>≤0.044-0.001). Additionally, enhanced <I>ARK5</I> mRNA expression was more frequent in tumors displaying RAF-mediated alterations and crossover pathways (<I>P</I>=0.01 and 0.03, respectively). Upregulation of <I>CEA</I> mRNA was more common in the advanced stages (<I>P</I>=0.034), while <I>VEGF</I> expression was greater in poorly differentiated or mucinous tumors (<I>P</I>=0.042). The high expressions of <I>MMP2</I> and <I>MMP9</I> were closely associated with invasion and migration of colorectal tumors and cell lines. Our results conclusively show that specific pathways of colorectal tumorigenesis are closely associated with characteristic tumor growth and invasion.</P>

포스터 발표 : 포스터 연제 ; 낭창성신염에서 Mycophenolate mofetil과 Prednisolone의 병합치료효과

진은선 ( Jin Eun Seon ),임천규 ( Im Cheon Gyu ),김희진 ( Kim Hui Jin ),이태원 ( Lee Tae Won ),김명재 ( Kim Myeong Jae ) 대한신장학회 2000 춘계학술대회 초록집 Vol.19 No.2

Genome-wide identification of chemosensitive single nucleotide polymorphism markers in gastric cancer.

Ha, Ye Jin,Yoon, Sang Nam,Jeon, Yeo Jin,Cho, Dong Hyung,Roh, Seon Ae,Kim, Byung Sik,Kim, Hee Jin,Kim, Seon Young,Kim, Yong Sung,Kim, Jin Cheon Potamitis Press 2011 Anticancer research Vol.31 No.12

<P>A chemosensitive single nucleotide polymorphism (SNP) discovery schema is presented that utilizes (i) genome-wide SNP screening, with a human SNP array and an in vitro chemosensitivity assay, in 93 patients with gastric cancer (GC), and (ii) biological utility assessment using cell viability assays of transfected GC cells. Cytotoxicity analysis showed that most of the MKN1 and SNU638 clones transfected with the G allele of Deoxyribonuclease II beta (DNASE2B) rs3738573 were more sensitive to docetaxel than those with the C allele (p0.001-0.029) and most of the AGS and SNU638 clones transfected with the T allele of 5-hydroxytryptamine receptor IE (HTRIE) rs3828741 were more sensitive to paclitaxel than those with the C allele (p0.001-0.019). Our findings show that the two novel markers, DNASE2B rs3738573 and HTR1E rs3828741, have potential for improving the prediction of chemosensitivity of GC patients.</P>

Clinical assessment and identification of immuno-oncology markers concerning the 19-gene based risk classifier in stage IV colorectal cancer

Lee, Jong Lyul,Roh, Seon Ae,Kim, Chan Wook,Kwon, Yi Hong,Ha, Ye Jin,Kim, Seon-Kyu,Kim, Seon-Young,Cho, Dong-Hyung,Kim, Yong Sung,Kim, Jin Cheon Baishideng Publishing Group Inc 2019 WORLD JOURNAL OF GASTROENTEROLOGY Vol.25 No.11

<P><B>BACKGROUND</B></P><P>Genomic profiling of tumors has contributed to the understanding of colorectal cancer (CRC), facilitating diagnosis, prognosis and selection of treatments, including targeted regimens. A report suggested that a 19-gene-based risk classifier (TCA19) was a prognostic tool for patients with stage III CRC. The survival outcomes in patients with stage IV CRC are still poor and appropriate selection of targeted therapies and immunotherapies is challenging.</P><P><B>AIM</B></P><P>To assess clinical implication of TCA19 in patients with stage IV CRC, and to identify TCA19 with involvement in immune-oncology.</P><P><B>METHODS</B></P><P>A retrospective review of the medical records of 60 patients with stage IV CRC was conducted, assessing clinicopathological variables and progression-free survival (PFS). TCA19 gene expression was determined by quantitative polymerase chain reaction (qPCR) in matched normal and tumor tissues taken from the study cohort. Expression of potential immune-oncology regulatory proteins and targets was examined by immunohistochemistry (IHC), western blot, immunofluorescence staining in tissues from a validation cohort of 10 patients, and in CRC cell lines co-cultured with monocyte <I>in vitro</I>.</P><P><B>RESULTS</B></P><P>In the patients with TCA19 score higher than the median, the PFS rates of eight patients who received the targeted regimens were significantly higher than the PFS rates of four patients who received 5-fluorouracil-based regimen (<I>P</I> = 0.041). In multivariate analysis, expression of signaling lymphocytic activation molecule family, member 7 (SLAMF7) and triggering receptor expressed on myeloid cells 1 (TREM1) was associated with PFS in the 60-patient cohort. After checking another 10 validate set, the expression of the IHC, the level of real-time qPCR, and the level of western blot were lower for SLAMF7 and higher for TREM7 in primary and metastatic tumors than in normal tissues. In CRC cells expressing SLAMF7 that were co-cultured with a monocytic cell line, levels of CD 68 and CD 73 were significantly lower at day 5 of co-culture than at day 0.</P><P><B>CONCLUSION</B></P><P>The TCA19 score might be prognostic for target-regimen-specific PFS in stage IV CRC. Down-regulation of SLAMF7 and up-regulation of TREM1 occur in primary and metastatic tumor tissues.</P>

Plasma Osteopontin Is a Useful Diagnostic Biomarker for Advanced Non-Small Cell Lung Cancer

( Seon Sook Han ),( Seung Joon Lee ),( Woo Jin Kim ),( Dong Ryeol Ryu ),( Jun Yeon Won ),( Shin Young Park ),( Myeong Ju Cheon ) 대한결핵 및 호흡기학회 2013 Tuberculosis and Respiratory Diseases Vol.75 No.3

Background: Osteopontin (OPN) and carbonic anhydrase IX (CAIX), which are expressed on the surface of tumor cells, are associated with hypoxia during tumor development and progression. However, the roles of these proteins in the plasma of patients with non-small cell lung cancer (NSCLC) are poorly understood. Herein, we hypothesized that plasma OPN and CAIX levels could be used as diagnostic and prognostic tumor markers in patients with NSCLC. Methods: Fifty-three patients with NSCLC and 50 healthy control subjects were enrolled. We selected controls without malignancy and matched them with NSCLC patient cases according to age and gender. Blood samples were collected at the time of diagnosis; the plasma levels of OPN and CAIX were measured by enzyme-linked immunosorbent assays. Results: The plasma levels of OPN in the patients with NSCLC were significantly elevated as compared to those in the controls (p=0.016). However, there was no difference in the plasma level of CAIX between the NSCLC patients and controls. NSCLC patients with a distant metastasis had a remarkable increase in plasma OPN compared with patients without metastasis (p=0.026), but no such correlation was found for CAIX. There was no difference in overall survival rates according to the plasma level of OPN between the two groups (by Kaplan-Meier survival analysis). Conclusion: Plasma OPN levels were elevated in patients with NSCLC as compared with the controls, with greater elevation of OPN levels in the advanced stages of disease. Therefore, plasma OPN may have utility as a diagnostic, but not prognostic, biomarker of advanced NSCLC.

Characterization of biological responses of colorectal cancer cells to anticancer regimens

Seon Ae Roh,Eun Young Choi,Dong Hyung Cho,Yong Sik Yoon,Tae Won Kim,Yong Sung Kim,Jin Cheon Kim 대한외과학회 2012 Annals of Surgical Treatment and Research(ASRT) Vol.83 No.1

Purpose: Identification of subgroups of patients who differ in their response to treatment could help to establish which of the best available chemotherapeutic options are best, based on biological activity. In metastatic colorectal cancer (CRC), novel molecular-targeted agents that act on pathways that regulate cell growth, the cell cycle, apoptosis, angiogenesis, and invasion are being developed. Here, we employed an in vitro chemosensitivity assay to evaluate the biological efficacy of conventional monotherapies and combination chemotherapy with targeted drugs. Methods: The chemosensitivities of 12 CRC cell lines to the established regimens FOLFOX (5-fluorouracil [5-FU] + leucovorin + oxaliplatin) and FOLFIRI (5-FU + leucovorin + irinotecan) and to therapy with these regimens in combination with the biologically targeted drugs bevacizumab or cetuximab were comparatively evaluated for their effects on apoptotic and autophagic cell death processes, angiogenesis, and invasion. Results: Each of the chemotherapeutic regimens promoted apoptotic cell death and invasion. All drug regimens caused significantly greater apoptotic cell death with activation of caspase-3 in SW480 cells compared to other cells, effects that were associated with a remarkable reduction in matrix metalloproteinase-9 activity. The FOLFOX regimen more effectively promoted apoptotic cell death, angiogenesis, and invasion than the FOLFIRI regimen. Combination therapy with FOLFOX/FOLFIRI regimen and bevacizumab produced a moderate angiogenesis-blocking effect in most cell lines. Conclusion: The results validate our in vitro chemosensitivity assay, and suggest that it may be applied to help determine adequate regimens in individual CRC patients based on the biological characteristics of their tumors.