[보고서]위장관암 분자표적 연구센터

정영도

보고서 정보

주관연구기관

전남대대학교병원

연구책임자

정영도

참여연구자

이재혁 , 박영규 , 정익주 , 심현정

보고서유형

최종보고서

발행국가

대한민국

언어

한국어

발행년월

2016-07

과제시작연도

2015

주관부처

보건복지부
[Ministry of Health & Welfare(MW)(MW)

연구관리전문기관

국립암센터
National Cancer Center

등록번호

TRKO201700009069

과제고유번호

1465017800

사업명

암연구소및국가암관리사업본부운영(구.국립암연구소운영)(연구개발사업비)

DB 구축일자

2017-11-04

키워드

위암.대장암.분자표적.암 표지자.세포분자치료.stomach cancer.colon cancer.molecular targeting.biomarker.cell and gene therapy.

DOI

https://doi.org/10.23000/TRKO201700009069

표 Mechanism of carcinogenesis by methylation
표 Multistep carcinogenesis induced by genetic and epigenetic events
표 Epigenetics-missing piece in gene expression
표 Global depiction of epigenetic alterations during oncogenesis
표 The implication of epigenetic silencing in the hallmarks of cancer
표 Integrative genomic analysis of gastric cancer
표 Sodium bisulfite modification and MSP-PCR
표 Levels of circulating DNA
표 Sodium bisulfite modification of DNA and multiplex MSP
표 Flow chart of current and potential applications of circulating tumor cell cell-free nucleic acids technologies
표 Methodologies for detecting circulating tumor DNA
표 Genetic alterations detectable in circulating cell-free tumor DNA
표 Computer-generated reconstruction of CTC images by semi-automated fluorescence-based microscopy system
표 Detection of tumor-specific DNA mutations in the blood of patients to monitor response and relapse with targeted therapies
표 위암에서 E-cadherin에 대한 Pyrosequecning예
표 Principle of melting analysis for methylation detection
표 Representative examples of MS-HRM for MGMT in gastric carcinoma
표 MSP analysis of E-cadherin and MGMT in plasma samples of gastric carcinoma patients
표 위암 및 대장암 환자의 혈장DNA내 DNA메틸화 표지자의 검출율
표 Affinity-based isolation of methylated DNA
표 후성유전학 데이터 분석 도식도
표 Tissue microarray of colon cancer
표 Immunohistochemical staining in tissue array samples of stomach cancer
표 Stomach cancer tissue microarray composed of total 26 paired normal and cancer tissues. Left is a thumbnail and right is a cancer spot magnified by 50x. This array is stained with anti-p16 antibody
표 대장 샘종과 암종에서 MSP를 이용한 hMLH1, hMSH2 및 MGMT 유전자의 메틸화와 해당 조직의 hMLH1면역조직화학적 염색결과
표 대장암 원발병소와 전이병소에서 E-cadherin 및 N-cadherin의 면역조직화학적 발현과 메틸화 결과
표 노년층 및 약년층 위암의 임상병리학적 특징
표 노년층 및 약년층 위암의 MMR 유전자메틸화 분석
표 위암에서 TRAIL 수용체와 caspase8의 메틸화 분석결과
표 위암에서 TRAIL 수용체 유전자의 메틸화와 임상병리학적 특징
표 샘종과 동반된 대장암에서 vimentin 유전자의 메틸화 분석결과
표 대장암에서 vimentin에 대한 면역조직염색 결과
표 조기위암과 진행성 위암에서 TCF4유전자의 메틸화분석; 정성적인 MSP와 정량적인 PS방법비교
표 위암환자의 연령증가에 따른 TCF4유전자의 메틸화의 정량적 변화와 환자의 예후와의 관련성
표 정상위조직, 조기위암 및 진행성 위암에서 COX2유전자의 메틸화를 MSP를 이용 정성적으로 분석함
표 조기위암과 진행성 위암에서 COX2유전자의 메틸화를 PS를 이용 정량적으로 분석함
표 위암에 COX2유전자의 메틸화 환자의 생존율과의 상관성을 보여줌
표 E-cadherin 단백질은 일반적으로 정상점막에서 발현이 잘 유지되는 것으로 알려져 있다 (Figure 2A). 그러나 유전자 프로모터에 메틸화를 동반한 다수의 증례에서 종양세포에서 발현이 억제되어 있었으며 (Figure 2B), 종양 주변의 정상점막에서도 일부 발현이 소실되어 있는 소견을 보여 (Figure 2C), 일부 종양 주 변 정상 점막에서는 종양으로 전환되지 않았더라도 E-cadherin이 소실되는 소견을 보이는 것을 확인할 수 있었 음
표 The MSP analysis of miRNA genes methylation in normal mucosa, margins,and GC. Methylation frequency was significantly increased in GC
표 Clinicopathological features of GC patients by promoter methylation miRNA genes
표 Correlation between the CIMP status and the clinicopathological parameters as well as MSI status in CRC
표 직접염기서열분석법(위)과 Pyrosquencing법(아래)에 의한 KRAS codon12의 돌연변이 GGT>GAT
표 직접염기서열분석법(위)과 Pyrosquencing법(아래)에 의한 KRAS codon13의 돌연변이 GGC>GAC
표 Pyrosequencing법에 의한 BRAF codon600의 돌연변이 GTG>GAG
표 Prevalence of KRAS mutation (codon 12 and 13) in stage 3-4 CRC without metastasis
표 Prevalence of KRAS mutation (codon 12 and 13) in primary CRC with metastasis
표 Prevalence of KRAS mutation (codon 12 and 13) in metastatic CRC
표 Prevalence of BRAF mutation (codon 600) in non-metastatic stage 3-4 (n=53), primary (n=51) and　metastatic CRC
표 Representative MS-HRM assay for p15, p16, MGMT, BLU, DAPK1, and GADD45G
표 Representative of normalized melting curves of MS-MSP
표 The frequency of promoter methylation of p15, p16, MGMT, BLU, DAPK1, and GADD45G genes in normal gastric and cancer tissues as well as plasma/serum of gastric cancer patients
표 Frequencies of aberrant promoter methylation of p15, p16, MGMT, BLU, DAPK1, and GADD45G genes in normal gastric and cancer tissues as well as plasma/serum of gastric cancer patients
표 Distribution of a number of methylated genes in tumor and plasma/serum in gastric cancer patients
표 Representative MSP assay for miR200-429, miR200-141, and E-cadherin gene methylation in gastric cancer
표 Proportion of cases with methylation of miR200 family gastric cancer
표 Immunohistochemical staining shows expression of ZEB1, and MUC1 in gastric cancer
표 Correlation between abnormal gene protein expression and gene promoter methylation in gastric cancer
표 Expression of EMT marker genes by RT-PCR 35 cycles
표 Expression of EMT proteins by wester blot analysis
표 Expression of Stemness marker genes by RT-PCR 35cycles
표 Investigation of promoter methylation of mir200 family and CDH1 genes in TMK1 cell line
표 Conversion of promoter methylation status of mir200 family and CDH1 genes by 5-aza-C treatment in TMK1 cell line
표 Expression of CDH1 and MUC1, the representative target genes of mir200 family, by qRT-PCR in cell lines SNU638, AGS, and TMK1
표 Expression of mir200 family members by qRT-PCR in cell lines SNU638, AGS, and TMK1
표 ZEB1 knockdown using siRNA in U251 and T98G cell lines, confimed by RT-PCR and western blot analysis
표 Invasion and migration assay after performing ZEB1 knock-down in U251 and T98G cell-lines
표 In comparison, ZEB1 knockdown using siRNAs in gastric cancer cell lines, AGS, TMK1 and SNU638, has not been established yet. Trials on ZEB1 knockdown is being performed using various siRNAs
표 Results from the locus-by-locus examination of differential methylation between right- and left-colon adenomas. (a) Volcano plot based on the locus-by-locus analysis. Points represent the –log10(P-value) obtained from testing the difference in methylation between right- and left-colon adenomas, adjusted for subject age and gender. Dotted line indicates –log10(0.05) and the dashed line represents the Bonferroni threshold (ie, – log10(0.05/no. of tests)). (b) Distribution of significant probes (those significant at the Bonferroni threshold) across CpG islands, shores, shelves, and oceans
표 Methylation status between right- and left-colon adenomas for PRAC (a) and CDX2 (b). Points represent the median methylation status for left- and right-colon adenomas and lines represent the locally weighted polynomial smoothed methylation status across the profiled CpGs associated with that gene
표 Heat map of the 168 significantly differentially methylated CpG loci between rightand left-colon adenomas. Methylation values are presented as unmethylated (yellow) to methylated (blue). Rows are represented by the 168 differentially methylated loci and columns represent subjects who are grouped based on adenoma side. On the right-hand side of the heat map is a color side bar, which indicates the island status for the 168 CpG loci. Above the heat map are color side bars that indicate smoking status, polyp size, gender, and age for the study subjects. Red and green dotted boxes indicate two subgroups of left-colon adenoma subjects, referred to as subgroups 1 and
표 Immunoreactivity for CDX2 (A) was reduced in some (4/6), but not all, adenomas that showed CDX2 hypermethylation by array analysis. However, all six adenomas with CDX2 hypermethylation showed aberrant nuclear and/or cytoplasmic localization of beta-catenin (B)
표 The results of MSI in early onset gastric cancer
표 CIMP status of promoter DNA methylation in early onset gastric cancer
표 (A) Lack of E-cadherin expression in diffuse gastric cancer with no hypermethylation, compared to normal gastric mucosa (inlet). (B) Relative CDH1 expression normal to tumor tissue in early onset gastric cancer. (C), Representative examples of methylation analysis of E-cadherin gene in early onset gastric cancer. The PCR products of the lanes marked U show the presence of unmethylated templates of each gene, whereas the products in the lanes marked M indicated the presence of methylated templates
표 Methylation analysis of CDH1 gene of normal and tumor tissue in early onset gastric cancer
표 Clustering and heatmap representation of dichotomous epigenetic silencing calls. We identified 769 genes that were silenced by DNA methylation in at least 5% of the tumours. The epigenetic silencing calls of each gene in 100 tumor samples are indicated by using a black (yes) and gray (no) color scheme. Genes are ordered based on a hierarchical clustering with Ward’s method on the Jaccard Distance, a distance measure that best suits binary data. CDKN2A and MLH1 DNA methylation status of each tumor sample are also shown as bars above the heatmap. Samples are grouped according to the four major molecular subtypes indicated as a vertical colour bar at the top
표 CAV1발현을 나타내는 대표조직사진. 종양세포(맨위), 종양사이질세포(중간), 뇌전이암의 종양세포(맨 아래)에서 양양성(왼쪽), 강양성(오른쪽) 염색강도를 나타내는 예시임. 아래 표1에서 분석된 결과에 따르면 CAV1은 원발암의 조직학적 유형에 따라 CAV1 발현율이 통계적으로 유의 하게 달라지는 것을 알 수 있으며 (p<0.001), 뇌전이가 있는 그룹에서 종양간질세포 CAV1 발현율이 상대적으 로 낮았음
표 원발암 조직에서 나이, 성별, 조직학적 유형, 원격전이 여부에 따른 CAV1 발현정도
표 CAV1발현을 포함한 임상병리학적 인자에 따른 환자생존율의 비교
표 암종세포주에서 CAV1 기저발현을 조사한 Western blot 밴드와 H1299와 H157에서 CAV1 siRNA를 처리하여 CAV1 발현 억제를 확인한 RT-PCR과 WB 결과
표 H1299와 H157에서 CAV1 siRNA를 처리하여 CAV1 발현을 억제 시켰을 때 invasion assay 결과와 wound healing migration assay 결과
표 암종세포주 H1299와 H157에서 CAV1 siRNA를 처리하여 CAV1 발현을 억제 시켰을 때 EMT인자의 발현변화를 western blot 방법으로 조사함
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표 signaling casca det.h e( A)I LLKe/vAeKlsT /oβf spirgontaeliinnsg rcealsacteadd e tow erIeL Km/AeKaTsu/rβe-dc autesninign iWnteesrtaecrtn wbiltoht tinTgβ. 4 (Bw)e reM odleectuelcetse d thbayt iamntmibuondoyp.r eIcmipmituantoiopnr ecuipsiitnagti ona nb y aIngtGi- wILaKs ulosceadli zaatsio nt hoef βc-onctartoeln. in( Cw)a s Indteetrecremlliunleadr ucysitnogp lasWmeics tefrrna ctiobnlost tiwnge.r e Nisuocllaetaerd aanndd eimqumaul nobloatmteodu ntuss ing oafn anetai-chβ -cawteenrien aunsteidb oadsy . nuLcalemairn -anAd acnydto pβla-stmuibcu lcino ntwroelrse. T(Dβ)4 -Nuupcrleegaur laltoecda lizaCtiaocno -o2f β-ceclalste ninw ains dimetmeucnteodfl uorescaenndc e qsutaanintiifnige.d Tbhye choismtopgarraemd tsoh owesm ptyr elavtievcet or incteonnstritoiless. SVDal.u eBsa r r=ep r1e0s eμnmt
표 Invasion ability of Tβ4-downregulated Caco-2 cells is restored by a GSK3β inhibitor
표 HOXB5 is frequently overexpressed in gastric cancer cells
표 HOXB5 induces cell migration and invasion in gastric cancer cells
표 HOXB5 is associated with the transcriptional activity of the β-catenin/TCF/LEF complex
표 β-catenin expression in gastric cancer cells was positively correlated with HOXB5 expression
$HOXB5 positively activates the β-catenin promoter. (A) Luciferase activity was measured in SNU638 cells after cotransfection with β-catenin promoter-reporter constructs and HOXB5 siRNA or noneffective control siRNA. Vertical lines are the putative HOXB5 binding sites. Values represent mean ± S.D. (B) Nucleotide sequences of the 5’flanking region (-4431/-4150) of the β-catenin promoter. The primers F1, F2, R1 and R2 were used to construct probes for an EMSA assay. (C) The binding activities of various length probes (P140, P160 and P282) with nuclear proteins were detected by EMSA. Symbols: *, free probe; **, probe-protein complex; † nonspecific-probe-protein complex. (D) ChIP was performed on chromatin from SNU638 cells using control anti-mouse IgG or two anti-HOXB5 antibodies form Origen (†) and Santa Cruz Biotechnology (††). ChIP fractions were analysed by PCR using the F1 and R1 primer set. IP, immunoprecipitation$ 표 HOXB5 positively activates the β-catenin promoter. (A) Luciferase activity was measured in SNU638 cells after cotransfection with β-catenin promoter-reporter constructs and HOXB5 siRNA or noneffective control siRNA. Vertical lines are the putative HOXB5 binding sites. Values represent mean ± S.D. (B) Nucleotide sequences of the 5’flanking region (-4431/-4150) of the β-catenin promoter. The primers F1, F2, R1 and R2 were used to construct probes for an EMSA assay. (C) The binding activities of various length probes (P140, P160 and P282) with nuclear proteins were detected by EMSA. Symbols: *, free probe; **, probe-protein complex; † nonspecific-probe-protein complex. (D) ChIP was performed on chromatin from SNU638 cells using control anti-mouse IgG or two anti-HOXB5 antibodies form Origen (†) and Santa Cruz Biotechnology (††). ChIP fractions were analysed by PCR using the F1 and R1 primer set. IP, immunoprecipitation
표 HOXB5 binds directly to the β-catenin promoter
표 The HOXB5-induced elevated invasion ability of SNU638 cells was abrogated by inhibition of β-catenin
표 MEIS2 is frequently overexpressed in colorectal cancer cells and its tumoral high expression correlated with advanced stage and shorter survival of colorectal cancer patients
표 Knockdown of MEIS2 inhibits cell growth and induces apoptosis in colorectal cancer cells (A)
표 Expression levels of apoptosis related genes in MEIS2 knockdown cells
표 MEIS2 regulates AKT1 expression and its signaling pathway
표 MEIS2 binds AKT1 promoter and regulates its transcriptional expression
표 AKT1 is overexpressed in colorectal cancer cells and its expression was significantly correlated with MEIS2 exptession
표 Knockdown of MEIS2 cannot induce apoptosis in p21 null mutant HCT-116 cells
표 Representative images of HOXC9 immunohistochemical staining in human gastric carcinomas
표 Immunohistochemical analyses of HOXC9 proten expression in gastric carcinomas
표 Survival curves using the Kaplan-Meier method by log rank test
표 Induction of apoptosis by HOXC9 knockdown
표 Effects ov HOXC9 specific shRNAs on apoptosis
표 Apoptotic effects of HOXC9 specific shRNA
표 The effect of Bcl-xL promoter activity by HOXC9 binding on Bcl-xL promoter region
표 HOXC9 binding to Bcl-xL promoter by chromatin immunoprecipitation and electrophoretic mobility-shift assay
표 Hemispleen liver metastasis model
표 Establishment of a high-potential peritoneal metastasis cell line
표 Expression of 90K gene and protein in colon cancer tissues and cells. (A) The expression of 90K was performed from extraneoplatic (Normal, N) and neoplastic lesion (Tumor, T) in 5 human colon patients by RT-PCR. (B) The expression of 90K protein in colon cancer cell lines was estimated by western blot. 293T cells were used negative control of 90K expression. 293T, HCT116, and SW480 cells were HLA class I positive but DKO, DLD1, HCT8 cells were HLA class I negative and cells
표 Binding Affinity of 90K peptides and control peptide fro HLA-A＊0201 molecule
표 Immunophenotype and T cell proliferating activity of DC1s pulsed with peptides
표 Characterization of 90K peptide-specific CTLs against T2 cells
표 Characterization of 90K peptide-specific CTLs against colon cancer cells
표 90K contributes to reduction in cell proliferation and motility
표 90K reverses the effects of galectins on Wnt/β -catenin activity
표 90K suppresses the canonical Wnt signaling pathway in a GSK-3β-independent manner
표 90K suppresses the canonical Wnt signaling pathway in a GSK-3β-independent manner. (E) Increasing amounts of 90K were transfected into 293T cells in the presence of LiCl (upper), or DN-β -TrCP (lower), and TOPFLASH activity was measured. (F) Influence of 90K on TOPFLASH activity (upper) and β-catenin protein level (lower) by S37A β-catenin
표 90K destabilizes the β-catenin with ISGylation -dependent ubiquitination
표 90K destabilizes the β-catenin with ISGylation-dependent ubiquitination
표 90K-induced degradation of β-catenin is mediated by CD9/CD82 complex
표 90K-induced degradation of β-catenin is mediated by CD9/CD82 complex
표 90K delays tumor growth and suppresses lung metastasis in vivo
표 The expression of 90K, CD9, CD82, β-catenin and galectins in human colon and metastatic liver tissues. The expression of 90K (A), CD9 (B), CD82 (C), β-catenin (D), galectin-3 (E), and galectin-1 (F) was examined by immunohistochemistry (dark brown color) in serially sectioned human colon tissues from stage I and IV CRC patients and in metastatic liver tissues from stage IV. In metastatic liver tissues, invading colon cancer cells (C) and adjacent hepatic tissues (H) are demarcated by the dotted line. Scale bar: 100 μm
표 90K expression is induced during DC development from human PBMC
표 90K knockdown affects the surface phenotype of DCs and cytokine secretion
표 Change of PI3K, MAPK, NF-kB pathway signaling after 90K knockdown in DCs
표 90K　treatment enhanced DCs development through TLR4 activation
표 Effects of 90K knockdown on DC-mediated T-cell proliferation
표 Cytokines were assessed by ELISA from the cultures of 90K knockdown and control DCs
표 CTLs of OT-1 mice were assessed using CSFE-labelled EG7 and EL4 as target cells
표 Tumor immunotherapy by 90K knockdown DCs. C57BL/6 mice were inoculated s.c. in the right flank area with EG7 tumor cells (5 x 105), and immunized with OVA peptide-pulsed 90K knockdown (si-90K) or 90K-normal (si-con) BMDCs. Upper panels show representative images of EG7 tumors on day 24 in tumor bearing mice. Tumor growth was monitored and represented as mean ± SD (n=5) (bottom panels). * p<0.01, compared with the group of mice vaccinated with OVA-pulsed control (si-con) DCs by unpaired Student’s test
표 Construction of recombinant GMIL18. (a) predicted amino acid sequence of the fusion transegene, GMIL18 protein consists of GMCSF and mature form of IL-18. (b) immunoblotting of conditioned supernatant from GMIL18 gene-modified HEK 293A cells with anti-mouse GMCSF and anti-mouse IL-18 antibodies (Lane M, protein size marker; Lane 1 and 4, supernatant from HEK 293A-GMIL18; Lane 2 and 5 recombinant mouse IL-18; Lane 3 and 6, recombinant mouse GMCSF). GMIL18 fusion protein indicated that have 37 kDa molecular weight. (c) quantity of GMIL18 fusion protein was measured by ELISA for levels of cytokine secretion from supernatant from HEK 293A-GMIL18
표 Fusion protein GMIL18 bifunctional bioactivity. (a) NSF-60 cell proliferation assays as determined by MTT incorporation after 48 hours of incubation with increasing concentrations of cytokines from conditioned supernatant of gene-modified HEK 293 cells. (b) mouse splenocytes IFN-r ELISA assays. Negative control, conditioned supernatant of pCMV empty vector transfected HEK 293 cells (a and b); Positive control, Lipopolysaccharide (LPS) (a) or recombinant GMCSF protein (b). * P < 0.05
표 H&E and IHC staining with anti-CD4 and anti-CD8 T cells in irradiated GMIL18 secreting vaccine treated mice tumors. Mouse colon cancer CT26 cells (1 x 106) were inoculated on the right flank region of BALB/c mice. The tumor size reached to about 0.5 ㎠ and then irradiated CT26GMIL18 (tumor vaccine) injected to tumor surrounded. The mice were sacrified at 5 days later, (A) Paraffin-embedded tumor sections were stained with H&E and IHC stained with anti-CD4+ and anti-CD8+ T-cells antibody. Immunohistochemical analysis of these tumor sections demonstrated that GMIL18 fusion protein significantly enhanced infiltration of CD4+ and CD8+ T in tumors compared with the vector only tumor vaccine-treated group. (B) GMIL18 group is NK cell heavy infiltration in the tumor site. Brown spots determined the infiltration of T cells
표 연구대상자의 기본특성 및 위험요인 비교
표 TCF7L2 (rs11196172) 유전형과 대립형질에 따른 환자군과 대조군의 분포
표 TCF7L2 (rs11196172) 유전형따른 대장암발생위험도 비교
표 당뇨와 비만유무에 따른 TCF7L2 (rs11196172) 유전형의 대장암 위험도의 차이

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