Relationship of novel genetically engineered mouse and the epithelial-mesenchymal transition in the metastastic progression of gastric cancers.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 3-3
Author(s):  
Hark K. Kim ◽  
Jun Won Park ◽  
Jeffrey E. Green
Keyword(s):  
Gastric Cancer ◽  
Lung Metastases ◽  
Genetically Engineered ◽  
Conditional Knockout ◽  
Metastatic Progression ◽  
Diffuse Type ◽  
Mesenchymal Transition ◽  
Gastric Cancers ◽  
Gastric Adenocarcinomas ◽  
E Cadherin

3 Background: By creating mice deficient in E-cadherin, Smad4, and p53, we evaluated whether and how Cdh1 heterozygosity may accelerate the development and progression of gastric cancer, in combination with loss of Smad4 and p53. Methods: Compound conditional knockout mice of Smad4, p53, and E-cadherin were mated with Pdx-1-Cre transgenic mice. Offsprings were monitored for the development of gastric adenocarcinomas. Results: Gastric adenocarcinomas spontaneously arose in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice and recapitulated human diffuse type gastric cancers in histopathology. Gastric adenocarcinoma was more frequent in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice than in Pdx-1-Cre;Smad4F/F;Trp53F/F mice. When compared to Pdx-1-Cre;Trp53F/F;Cdh1F/F mice, Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice developed gastric adenocarcinomas more rapidly, suggesting that Smad4 and E-cadherin cooperate to constrain the development of gastric adenocarcinomas. Lung metastases were identified in three Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice, but not in the other genotypes. The epithelial-to-mesenchymal transition (EMT), characterized by increased vimentin expression, was identified at the invasive tumor front of gastric adenocarcinomas arising in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice. This phenotype was less prominent in mice with intact E-cadherin or Smad4, indicating that the suppression of EMT by E-cadherin or Smad4 may reduce metastatic signaling pathways in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice. Conclusions: Loss of E-cadherin and Smad4 cooperate with p53 loss to promote the development and metastatic progression of gastric adenocarcinomas, with similarities to human diffuse type gastric cancer. Thus, our novel genetically-engineered mouse models reveal the importance of EMT in the metastatic progression of gastric cancers, providing a unique model to test agents targeting the metastatic progression in gastric cancers.

scholarly journals Competing Endogenous RNA Networks in the Epithelial to Mesenchymal Transition in Diffuse-Type of Gastric Cancer

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2741
Author(s):  
Natalia Landeros ◽  
Pablo M. Santoro ◽  
Gonzalo Carrasco-Avino ◽  
Alejandro H. Corvalan
Keyword(s):  
Gastric Cancer ◽  
Transcription Factors ◽  
Molecular Basis ◽  
Epithelial To Mesenchymal Transition ◽  
Diffuse Type ◽  
Competing Endogenous Rna ◽  
Mesenchymal Transition ◽  
Direct Targeting ◽  
E Cadherin

The diffuse-type of gastric cancer (DGC), molecularly associated with epithelial to mesenchymal transition (EMT), is increasing in incidence. Loss of E-cadherin expression is the hallmark of the EMT process and is largely due to the upregulation of the EMT-inducing transcription factors ZEB1/2, Snail, Slug, and Twist1/2. However, ncRNA, such as miRNA and lncRNAs, can also participate in the EMT process through the direct targeting of E-cadherin and other EMT-inducing transcription factors. Additionally, lncRNA can sponge the miRNA pool that targets these transcripts through competing endogenous RNA (ceRNA) networks. In this review, we focus on the role of ncRNA in the direct deregulation of E-cadherin, as well as EMT-inducing transcription factors. Based on the relevance of the ceRNA network hypothesis, and the lack of said networks in EMT, we performed a prediction analysis for all miRNAs and lncRNAs that target E-cadherin, as well as EMT-inducing transcription factors. This analysis resulted in novel predicted ceRNA networks for E-cadherin and EMT-inducing transcription factors (EMT-TFs), as well as the expansion of the molecular basis of the DGC.

The Lauren Classification Highlights the Role of Epithelialto- Mesenchymal Transition in Gastric Carcinogenesis: an Immunohistochemistry Study of the STAT3 and Adhesion Molecules Expression

2015 ◽  
Vol 24 (1) ◽  
pp. 77-83 ◽  
Author(s):  
Sergiu Susman ◽  
Raphaelle Barnoud ◽  
Frederique Bibeau ◽  
Francesco Borini ◽  
Marc Pocard ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Adhesion Molecules ◽  
Molecular Mechanisms ◽  
Gastric Carcinogenesis ◽  
Morphological Aspect ◽  
Nuclear Staining ◽  
Diffuse Type ◽  
Mesenchymal Transition ◽  
Gastric Tumors ◽  
E Cadherin

Background & Aims: Despite some recent advances, gastric cancer remains an important cause of death at world level. This indicates an absence of therapeutic options, stemming from the limited understanding of the molecular mechanisms involved in carcinogenesis. Nearly fifty years ago Lauren classified gastric cancers, according to the morphological aspect, as intestinal or diffuse. The phenotype of the cells indicates the presence of different molecular mechanisms, which can be approached in the light of recent data and identified with the help of current techniques. The best described are the germline/somatic mutations or the hypermethylations of the E-cadherin 1 CDH1 gene promotor.Methods. We analyzed 195 gastric tumors,120 intestinal and 75 diffuse type, using immunohistochemistry (tissue microarray TMA method) for pStat3Tyr705, E-cadherin, α-catenin and β-catenin; 985 spots of gastric tumors, distributed on 4 TMA blocks were analyzed. For pStat3Tyr705 we took the nuclear staining into account and for the adhesion molecules, membrane staining.Results. In our study, in the diffuse type gastric cancer, pStat3Tyr705 nuclear expression was statistically significantly increased (p=0.003). Also we observed a decreased expression of the adhesion molecules in the same type of gastric cancer (E-cadherin p<0.0001, α-catenin p<0.0001, β-catenin p<0.0001), suggesting that epithelial-to-mesenchymal transition (EMT) may be involved not only in gastric carcinogenesis, but also in resistance to treatment.Conclusion. The Stat3 role has been recently highlighted in carcinogenesis of the diffuse type of gastric cancer. We found that the morphological features of the diffuse type also suggest the involvement of EMT in this type of gastric cancer. Therefore, targeting the key molecules involved in this process may interfere with EMT process in the diffuse type of gastric cancer.

scholarly journals Genomic landscape of a mouse model of diffuse-type gastric adenocarcinoma

2021 ◽  
Author(s):  
Menghua Zhang ◽  
Itsuki Sugita ◽  
Daisuke Komura ◽  
Hiroto Katoh ◽  
Shu Shimada ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Transcription Factors ◽  
Mouse Model ◽  
Gastric Adenocarcinoma ◽  
Copy Number ◽  
Conditional Knockout ◽  
Human Gastric Cancer ◽  
Diffuse Type ◽  
Gastric Cancers ◽  
Diffuse Type Gastric Cancer

Abstract Background There is a need for a model of diffuse-type gastric cancer that captures the features of the disease, facilitates the study of its mechanisms, and aids the development of potential therapies. One such model may be Cdh1 and Trp53 double conditional knockout (DCKO) mice, which have histopathological features similar to those of human diffuse-type gastric cancer. However, a genomic profile of this mouse model has yet to be completed. Methods Whole-genome sequences of tumors from eight DCKO mice were analyzed and their molecular features were compared with those of human gastric adenocarcinoma. Results DCKO mice gastric cancers harbored single nucleotide variations and indel patterns comparable to those of human genomically stable gastric cancers, whereas their copy number variation fraction and ploidy were more similar to human chromosomal instability gastric cancers (perhaps due to Trp53 knockout). Copy number variations dominated changes in cancer-related genes in DCKO mice, with typical high-level amplifications observed for oncogenic drivers, e.g., Myc, Ccnd1, and Cdks, as well as gastrointestinal transcription factors, e.g., Gata4, Foxa1, and Sox9. Interestingly, frequent alterations in gastrointestinal transcription factors in DCKO mice indicated their potential role in tumorigenesis. Furthermore, mouse gastric cancer had a reproducible but smaller number of mutational signatures than human gastric cancer, including the potentially acid-related signature 17, indicating shared tumorigenic etiologies in humans and mice. Conclusions Cdh1/Trp53 DCKO mice have similar genomic features to those found in human gastric cancer; hence, this is a suitable model for further studies of diffuse-type gastric cancer mechanisms and therapies.

SETD1A to induce epithelial-mesenchymal transition to promote invasion and metastasis through epigenetic reprogramming of snail in gastric cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 241-241
Author(s):  
Jugang Wu ◽  
Jiwei Yu ◽  
Yan Gu
Keyword(s):  
Gastric Cancer ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Epigenetic Modification ◽  
Epigenetic Reprogramming ◽  
Migration And Invasion ◽  
Mrna Levels ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
E Cadherin

241 Background: Aberrant epigenetic modification induces oncogenes expression and promotes cancer development. The histone lysine methyltransferase SETD1A, which specifically methylates H3K4, is involved in tumor growth and metastasis, and its ectopic expression has been detected in aggressive malignancies. Our previous study had reported that SETD1A promoted gastric cancer (GC) proliferation and tumorigenesis. However, the function and molecular mechanisms of SETD1A in GC metastasis remain to be elucidated. Methods: Transwell migration and invasion assay were performed to determine GC cell migration and invasion. Lung metastasis assay was used to detect GC cell metastasis. Western Blot and Real-time qPCR were performed to measure the protein and mRNA levels, respectively. ChIP assay was performed to investigate the methylation of H3K4. The correlation between SETD1A and EMT associated key genes in GC were performed by bioinformatic analysis. Results: In this study, we found that overexpression of SETD1A promotes GC migration and invasion, whereas knockdown of SETD1A suppressed GC migration, invasion and metastasis. Furthermore, knockdown of SETD1A suppressed GC epithelial-mesenchymal transition (EMT) by increasing the expression of epithelial marker E-cadherin, and decreasing the expression of mesenchymal markers, including N-cadherin, Fibronectin and Vimentin. Mechanistically, knockdown of SETD1A reduced the EMT key transcriptional factors snail. SETD1A was recruited to the promoter of snail, where SETD1A could methylate H3K4. However, knockdown of SETD1A decreased the methylation of H3K4 on snail promoter. Rescue of snail restored SETD1A knockdown-induced GC migration and invasion inhibition. In addition, linear correlation between SETD1A and several key EMT genes, including E-cadherin, Fibronectin and snail, in GC specimens obtained from TCGA dataset. Conclusions: In summary, our data reveals that SETD1A mediated EMT process and induced metastasis through epigenetic reprogramming of snail.

scholarly journals Molecular Network Profiling in Intestinal- and Diffuse-Type Gastric Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3833
Author(s):  
Shihori Tanabe ◽  
Sabina Quader ◽  
Ryuichi Ono ◽  
Horacio Cabral ◽  
Kazuhiko Aoyagi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Drug Resistance ◽  
Signaling Pathways ◽  
Pathway Analysis ◽  
Rna Binding ◽  
Binding Protein ◽  
Diffuse Type ◽  
Mesenchymal Transition ◽  
Diffuse Type Gastric Cancer

Epithelial-mesenchymal transition (EMT) plays an important role in the acquisition of cancer stem cell (CSC) feature and drug resistance, which are the main hallmarks of cancer malignancy. Although previous findings have shown that several signaling pathways are activated in cancer progression, the precise mechanism of signaling pathways in EMT and CSCs are not fully understood. In this study, we focused on the intestinal and diffuse-type gastric cancer (GC) and analyzed the gene expression of public RNAseq data to understand the molecular pathway regulation in different subtypes of gastric cancer. Network pathway analysis was performed by Ingenuity Pathway Analysis (IPA). A total of 2815 probe set IDs were significantly different between intestinal- and diffuse-type GC data in cBioPortal Cancer Genomics. Our analysis uncovered 10 genes including male-specific lethal 3 homolog (Drosophila) pseudogene 1 (MSL3P1), CDC28 protein kinase regulatory subunit 1B (CKS1B), DEAD-box helicase 27 (DDX27), golgi to ER traffic protein 4 (GET4), chromosome segregation 1 like (CSE1L), translocase of outer mitochondrial membrane 34 (TOMM34), YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), ribonucleic acid export 1 (RAE1), par-6 family cell polarity regulator beta (PARD6B), and MRG domain binding protein (MRGBP), which have differences in gene expression between intestinal- and diffuse-type GC. A total of 463 direct relationships with three molecules (MYC, NTRK1, UBE2M) were found in the biomarker-filtered network generated by network pathway analysis. The networks and features in intestinal- and diffuse-type GC have been investigated and profiled in bioinformatics. Our results revealed the signaling pathway networks in intestinal- and diffuse-type GC, bringing new light for the elucidation of drug resistance mechanisms in CSCs.

scholarly journals Roles of E-cadherin and Noncoding RNAs in the Epithelial–mesenchymal Transition and Progression in Gastric Cancer

2019 ◽  
Vol 20 (12) ◽  
pp. 2870 ◽  
Author(s):  
Irina V. Bure ◽  
Marina V. Nemtsova ◽  
Dmitry V. Zaletaev
Keyword(s):  
Gastric Cancer ◽  
Cancer Cell ◽  
Rho Gtpase ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Cancer ◽  
Noncoding Rnas ◽  
Oncogenic Signaling ◽  
Control Of Gene Expression ◽  
Mesenchymal Transition ◽  
E Cadherin

The epithelial–mesenchymal transition (EMT) is thought to be at the root of invasive and metastatic cancer cell spreading. E-cadherin is an important player in this process, which forms the structures that establish and maintain cell–cell interactions. A partial or complete loss of E-cadherin expression in the EMT is presumably mediated by mechanisms that block the expression of E-cadherin regulators and involve the E-cadherin-associated transcription factors. The protein is involved in several oncogenic signaling pathways, such as the Wnt/β-catenin, Rho GTPase, and EGF/EGFR, whereby it plays a role in many tumors, including gastric cancer. Such noncoding transcripts as microRNAs and long noncoding RNAs—critical components of epigenetic control of gene expression in carcinogenesis—contribute to regulation of the E-cadherin function by acting directly or through numerous factors controlling transcription of its gene, and thus affecting not only cancer cell proliferation and metastasis, but also the EMT. This review focuses on the role of E-cadherin and the non-coding RNAs-mediated mechanisms of its expressional control in the EMT during stomach carcinogenesis.

scholarly journals Inactivation of the E-Cadherin Gene in Sporadic Diffuse-Type Gastric Cancer

2001 ◽  
Vol 14 (10) ◽  
pp. 942-949 ◽  
Author(s):  
Jennifer J Ascaño ◽  
Henry Frierson ◽  
Christopher A Moskaluk ◽  
Jeffrey C Harper ◽  
Franco Roviello ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Diffuse Type ◽  
Diffuse Type Gastric Cancer ◽  
E Cadherin

scholarly journals CLIC4 abrogation promotes epithelial–mesenchymal transition in gastric cancer

2019 ◽  
Vol 41 (6) ◽  
pp. 841-849 ◽  
Author(s):  
Baolong Wang ◽  
Jiqing Zheng ◽  
Qiongyuan Chen ◽  
Chaofan Wu ◽  
Yangxin Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Clinical Stage ◽  
Stem Cell Markers ◽  
Ags Cells ◽  
Mesenchymal Transition ◽  
Cancer Stem Cell Markers ◽  
Normal Tissues ◽  
Gastric Adenocarcinomas ◽  
Etoposide Treatment

Abstract Chloride intracellular channel protein 4 (CLIC4) has been implicated in different types of cancers, but the role of CLIC4 in the development of gastric cancer (GC) remains unknown. We analyzed the expression of CLIC4 in 102 pairs of gastric adenocarcinomas by western blot and real-time PCR. Our data revealed that the expression of CLIC4 is reduced in GC tumor tissues compared with adjacent normal tissues. The expression levels of CLIC4 correlate inversely with the clinical stage of GC. CLIC4 expression is lowest in MKN45 cells, which have the highest tumorigenic potential and express the highest levels of cancer stem cell markers CD44 and OCT4, compared with N87 and AGS cells. Exogenous overexpression of CLIC4 downregulated the expression of CD44 and OCT4, and inhibited migration, invasion and epithelial–mesenchymal transition (EMT). Moreover, anchorage-independent growth of GC cells was decreased and the cells became more sensitive to 5-fluorouracil and etoposide treatment when CLIC4 was overexpressed. The ability of N87 cells to form tumors in nude mice was enhanced when CLIC4 was silenced. We, for the first time, demonstrate that CLIC4 suppresses tumor growth by inhibiting cancer cell stemness and EMT.

scholarly journals Hyperinsulinemia promotes metastasis to the lung in a mouse model of Her2-mediated breast cancer

2013 ◽  
Vol 20 (3) ◽  
pp. 391-401 ◽  
Author(s):  
Rosalyn D Ferguson ◽  
Emily J Gallagher ◽  
Dara Cohen ◽  
Aviva Tobin-Hess ◽  
Nyosha Alikhani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mouse Model ◽  
Lung Metastases ◽  
Breast Cancer Incidence ◽  
Mesenchymal Cells ◽  
Tumor Formation ◽  
Metastatic Progression ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Incidence And Mortality

The Her2 oncogene is expressed in ∼25% of human breast cancers and is associated with metastatic progression and poor outcome. Epidemiological studies report that breast cancer incidence and mortality rates are higher in women with type 2 diabetes. Here, we use a mouse model of Her2-mediated breast cancer on a background of hyperinsulinemia to determine how elevated circulating insulin levels affect Her2-mediated primary tumor growth and lung metastasis. Hyperinsulinemic (MKR+/+) mice were crossed with doxycycline-inducible Neu-NT (MTB/TAN) mice to produce the MTB/TAN/MKR+/+ mouse model. Both MTB/TAN and MTB/TAN/MKR+/+ mice were administered doxycycline in drinking water to induce Neu-NT mammary tumor formation. In tumor tissues removed at 2, 4, and 6 weeks of Neu-NT overexpression, we observed increased tumor mass and higher phosphorylation of the insulin receptor/IGF1 receptor, suggesting that activation of these receptors in conditions of hyperinsulinemia could contribute to the increased growth of mammary tumors. After 12 weeks on doxycycline, although no further increase in tumor weight was observed in MTB/TAN/MKR+/+ compared with MTB/TAN mice, the number of lung metastases was significantly higher in MTB/TAN/MKR+/+ mice compared with controls (MTB/TAN/MKR+/+ 16.41±4.18 vs MTB/TAN 5.36±2.72). In tumors at the 6-week time point, we observed an increase in vimentin, a cytoskeletal protein and marker of mesenchymal cells, associated with epithelial-to-mesenchymal transition and cancer-associated fibroblasts. We conclude that hyperinsulinemia in MTB/TAN/MKR+/+ mice resulted in larger primary tumors, with more mesenchymal cells and therefore more aggressive tumors with more numerous pulmonary metastases.

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