EGFR and E-cadherin coregulated genes mediate the growth and metastasis of gastric cancer cells by ceRNA networks
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE222931 | GEO | 2023/01/27
REPOSITORIES: GEO
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2023-01-01 | E-MTAB-11936 | biostudies-arrayexpress
Project description:Background & Aims: E-cadherin expression disruption is commonly observed in epithelial cancers and metastasis. Such event is also recognized as a crucial step in gastric cancer (GC) initiation and progression. As aberrant expression of microRNAs often perturb the normal expression and function of pivotal cancer-related genes, we characterized and dissected a pathway initiated by loss of microRNA-101 that causes E-cadherin dysfunction through upregulation of EZH2 expression in GC. Methods: Microarrays were used to profile the expression of microRNAs in human GC. Array-CGH revealed DNA copy number changes that were validated by genomic quantitative PCR and Snapshot. Expression levels of microRNAs, mRNA and protein were determined by quantitative-real time PCR and western-blot/co-immunofluorescence. CDH1 inactivating mechanisms were analyzed. Gain and loss of function experiments were done in KatoIII cells. E-cadherin functionality was assessed by immunofluorescence and flow cytometry. Results: MiR-101 expression was significantly decreased in tumors in comparison with normal gastric mucosas (P<.0001). In 65% of the analyzed GC cases, miR-101 downregulation was caused by deletions and/or microdeletions at miR-101-2 locus. EZH2 overexpression and consequent loss/aberrant E-cadherin expression was found in concomitance with miR-101 downregulation in 41% of the analyzed GC cases. This occurred preferentially in cases retaining allele(s) untargeted by classical CDH1 inactivating mechanisms. MiR-101 gain of function experiments or direct inhibition of EZH2, led to a strong depletion of endogenous EZH2 protein and consequent rescue of functional E-cadherin at the cell membrane, mimicking results obtained with clinical GC samples. Conclusions: Deletions and/or microdeletions at miR-101-2 locus underlying mature miR-101 downregulation and consequent EZH2 overexpression represented a novel cascade of genetic events leading to E-cadherin disruption, preferentially affecting the intestinal-type of GC. In the present study, 37 primary GCs and a pool of 10 normal gastric mucosas were used to acquire the expression of 703 known human mature miRNAs deposited in the Sanger miRBase Sequence Database, Release 10.0 (http://microrna.sanger.ac.uk), as well as 393 novel human miRNAs discovered through deep sequencing and validated by qRT-PCR and array profiling (NCodeM-bM-^DM-" Human miRNA microarray probe set V3 from Invitrogen). The 10 normal gastric mucosa RNA samples were pooled to obtain the normal gastric reference sample, which was labelled and hybridised four times to check arrays' reproducibility.
2012-07-31 | E-GEOD-33743 | biostudies-arrayexpress
Project description:To elucidate the mechanism of the epithelial-mesenchymal transition observed in MCF10A cell with HSF1 overexpression, we performed RNA-seq analyses. They revealed that cadherin signaling pathway (P00012) was the most enriched in the set of genes down-regulated in these cells. In addition to CDH1 and CDH2, 19 genes encoding protocadherins also showed reduced expression. Among the genes most severely affected in cells with HSF1 overexpression were many genes encoding cell adhesion or cytoskeleton-organizing proteins (e.g. GJA5, NID2, TUBA1A, MFAP5, TAGLN were inhibited, TTC25, CADM3, IQGAP2, SDK2, CEACAM6, FAT2 were upregulated).
2023-11-02 | GSE241795 | GEO
Project description:Background & Aims: E-cadherin expression disruption is commonly observed in epithelial cancers and metastasis. Such event is also recognized as a crucial step in gastric cancer (GC) initiation and progression. As aberrant expression of microRNAs often perturb the normal expression and function of pivotal cancer-related genes, we characterized and dissected a pathway initiated by loss of microRNA-101 that causes E-cadherin dysfunction through upregulation of EZH2 expression in GC. Methods: Microarrays were used to profile the expression of microRNAs in human GC. Array-CGH revealed DNA copy number changes that were validated by genomic quantitative PCR and Snapshot. Expression levels of microRNAs, mRNA and protein were determined by quantitative-real time PCR and western-blot/co-immunofluorescence. CDH1 inactivating mechanisms were analyzed. Gain and loss of function experiments were done in KatoIII cells. E-cadherin functionality was assessed by immunofluorescence and flow cytometry. Results: MiR-101 expression was significantly decreased in tumors in comparison with normal gastric mucosas (P<.0001). In 65% of the analyzed GC cases, miR-101 downregulation was caused by deletions and/or microdeletions at miR-101-2 locus. EZH2 overexpression and consequent loss/aberrant E-cadherin expression was found in concomitance with miR-101 downregulation in 41% of the analyzed GC cases. This occurred preferentially in cases retaining allele(s) untargeted by classical CDH1 inactivating mechanisms. MiR-101 gain of function experiments or direct inhibition of EZH2, led to a strong depletion of endogenous EZH2 protein and consequent rescue of functional E-cadherin at the cell membrane, mimicking results obtained with clinical GC samples. Conclusions: Deletions and/or microdeletions at miR-101-2 locus underlying mature miR-101 downregulation and consequent EZH2 overexpression represented a novel cascade of genetic events leading to E-cadherin disruption, preferentially affecting the intestinal-type of GC.
2012-08-01 | GSE33743 | GEO
Project description:E-cadherin, a protein encoded by the CDH1 gene is the dominant epithelial cell adhesion molecule playing a crucial role in epithelial tissue polarity and structural integrity. The progression of 90% or more carcinomas is believed to be mediated by disruption of normal E-cadherin expression, subcellular localization or function. Despite the strong correlation between E-cadherin loss and malignancy the mechanism through how this occurs is not known in most sporadic and hereditary epithelial carcinomas. Previous works have shown the importance of CDH1 intron 2 sequences for proper gene and protein expression supporting the possibility of these being cis-modulators of E-cadherin expression/function. but when co-expressed it led to reduced cell-cell adhesiveness, increased invasion and angiogenesis. By expression array analysis, IFITM1 and IFI27 levels were found to be increased upon CDH1a overexpression. Importantly, CDH1a was found to be de novo expressed in gastric cancer cell lines when compared to normal stomach. Results: In this sense we have searched for additional CDH1 transcripts arising from intron 2. From the four found, one (CDH1a) was demonstrated to be tissue specific and to be translated in vivo. When overexpressed in an E-cadherin negative context CDH1a replaced the canonic protein functions Conclusions: We have demonstrated, for the first time, transcripts arising from CDH1 intron 2. One of these, CDH1a, was found to modulate E-cadherin function representing a novel mechanism underlying invasion and angiogenesis in epithelial cancers and opening the way for novel therapeutic approaches. Total RNA obtained from human gastric tubular adenocarcinoma Mkn28 cell line. Three independent replicas of each conditions(i.e pLenti transduced cell lines overexpressing CDH1a , pLenti with empty vector and pLenti transduced cell lines overexpressing wild type CDH1) has been employed.
2012-08-01 | E-GEOD-32540 | biostudies-arrayexpress
Project description:BACKGROUND & AIMS: Gastric cancer is the second most frequent cause of death from cancer in the world, diffuse-type gastric cancer (DGC) exhibiting a poor prognosis. Germline mutations of CDH1, encoding E-cadherin, have been reported in hereditary DGCs, and genetic and/or epigenetic alterations of CDH1 are frequently detected in sporadic DGCs. Genetic alterations of TP53 are also frequently found in DGCs. To examine the synergistic effect of loss of E-cadherin and p53 on gastric carcinogenesis, we established a mouse line in which E-cadherin and p53 are specifically inactivated in the stomach parietal cell lineage. METHODS: We crossed Atp4b-Cre mice with Cdh1loxP/loxP and Trp53loxP/loxP mice, and examined the gastric phenotype of Atp4b-Cre+;Cdh1loxP/loxP;Trp53loxP/loxP mice. RESULTS: Non-polarization of E-cadherin-negative parietal cells and proton pump-negative atypical foci were observed in the transgenic mice. Intramucosal cancers and invasive cancers composed of poorly differentiated carcinoma cells and signet ring cells, which were histologically very similar to those in humans, were found from 6 and 9 months, respectively. Fatal DGCs developed at 100% penetrance within a year, frequently metastasized to lymph nodes, and had tumorigenic activity in immunodeficient mice. Gene expression profiling analyses also revealed that DGCs in the E-cadherin/p53-deficient mice resembled human DGCs. CONCLUSIONS: Our mouse line is the first genetically modified mouse model of DGC and very useful for clarifying the mechanism underlying gastric carcinogenesis, and provides a new approach to the treatment and prevention of DGC because of morphological and biochemical similarities with human DGC. Two-condition experiment, Gastric cancer vs. normal gastric mucosal tissues. Biological replicates: pooled control sample from five normal gastric mucosal tissues, three replicates from diffuse-type gastric cancer.
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Project description:Identifying PDEF regulated genes may shed light on the mechanism by which PDEF may induce breast cancer progression. To that purpose, we have used the MCF-7 human breast tumor cell line model to identify PDEF induced genes. Briefly, PDEF expression was down regulated by shRNA in MCF-7 cells and RNA probes from PDEF-down regulated and control MCF-7 cells were used to screen the Affymetrics HG-U133A Gene Chips. This analysis found 62 genes that were induced 2-fold or higher by PDEF. Further analysis of 3 of these genes namely S100A7, CEACAM6 and B7-H4 in primary breast tumors showed CEACAM6 as a frequently elevated and co-exressed gene with PDEF in these tumors. We previously reported a role for PDEF (prostate derived Ets transcription factor) in breast tumor progression and its association with poor clinical outcome in ER+ breast cancer. To gain further insights into PDEF action in breast cancer, we down regulated PDEF expression by shRNA in MCF-7 human breast tumor cell line, and screened the HG-U133A human gene chips with probes from PDEF down-regulated and control MCF-7 cells. This analysis identified CEACAM6 as one of the genes induced by PDEF. Further analysis of CEACAM6 expression in relation to PDEF in 93 ER+ primary breast tumors showed largely concordant expression of these molecules. To our knowledge, our findings of CEACAM6 as a PDEF induced gene and their elevated co-expression in breast cancer have not been described before. Data from one replicate experiment is included as a representative example of the data obtained. HG-U133A gene chip pairs were screeened with biotinylated RNA probes from PDEF-down regulated MCF-7 cells (experimental) or from control MCF-7 cells.
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2005-05-22 | E-GEOD-2685 | biostudies-arrayexpress
Project description:We have tried to identify molecules associated with lymph node ratio expression by microarray. Expression microarray data prioritized gene candidates according to average expression ratio and its frequency. Among these genes, we examined particular EGFR expression by immunohistochemistry (IHC) in 167 advanced gastric cancer. We compared tumor specimens with high LNR (n=4) with those with low one (n=4) at mRNA level by Affymetrix microarray (harboring 54,675 genes) in stage III gastric cancer. We then prioritized the expression data, and enriched genes correlated with LNR, and finally validated EGFR as such candidates in primary advanced gastric cancer who underwent standard treatment (n=167).
2013-10-26 | E-GEOD-51725 | biostudies-arrayexpress
Project description:Three transcription factors KLF5, GATA4 and GATA6 are recurrently amplified in multiple gastric cancer cohorts, representing one type of lineage-survival oncogenes in gastric cancer. ChIP-Seq analysis of these three factors in multiple cell lines revealed that significant number of genomic sites are co-occupied by KLF5 and GATA4 and/or GATA6. Integrative analysis of ChIP-Seq and gene expression identified several targets of the three transcription factors in both cell lines and primary tumors, including HNF4A. These results suggest that KLF5, GATA4 and GATA6 interact and co-operate to regulate HNF4A and other genes to promote tumorigenesis in gastric cancer. ChIP-Seq experiments of KLF5, GATA4 and GATA6 were performed in three gastric cancer cell lines YCC3, AGS and KATOIII
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