Gene expression signatures of highly metastatic gallbladder cancer cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE106671 | GEO | 2017/11/09
SECONDARY ACCESSION(S): PRJNA417578
REPOSITORIES: GEO
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Project description:Gallbladder cancer (GBC) comprises the most common biliary tract cancer (BTC). However, GBC is a rare disease often manifesting as aggressive malignancy due to its late diagnosis and resistance to chemotherapy. The identification of molecular drivers of GBC and identification of targeted therapies is still urgently needed. This study combined proteomic analysis of GBC patient samples, functional and molecular characterization of potential oncogenes, and identification of potential therapy strategy for GBC. We identified Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) as one of the strongest and most significant upregulated proteins in GBC samples. Functional analysis and in vivo mouse models revealed that CEACAM6 supported the initial steps of cancer metastasis by decreasing cell adhesion while promoting migration and invasion of GBC cells. BirA-BioID followed by mass-spectrometry revealed Integrin Beta-1 (ITGB1) and Protein Kinase C Delta (PRKCD) as direct molecular and functional partners of CEACAM6 in supporting GBC cell migration through regulation of ERK and AKT downstream target genes MMP13, MMP14, and OCLN. Conversely, CEACAM6 knockdown abolished GBC aggressiveness, and treatment using AKT inhibitor Capivasertib and ERK inhibitor Ulixertinib counter-acted the CEACAM6-induced migration.These findings demonstrate that CEACAM6 is crucial for gallbladder oncogenesis through ERK and AKT signaling, providing insights into the design of therapeutic strategies for GBC.
2024-10-30 | GSE243304 | GEO
Project description:Gallbladder cancer (GBC) comprises the most common biliary tract cancer (BTC). However, GBC is a rare disease often manifesting as aggressive malignancy due to its late diagnosis and resistance to chemotherapy. The identification of molecular drivers of GBC and identification of targeted therapies is still urgently needed. This study combined proteomic analysis of GBC patient samples, functional and molecular characterization of potential oncogenes, and identification of potential therapy strategy for GBC. We identified Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) as one of the strongest and most significant upregulated proteins in GBC samples. Functional analysis and in vivo mouse models revealed that CEACAM6 supported the initial steps of cancer metastasis by decreasing cell adhesion while promoting migration and invasion of GBC cells. BirA-BioID followed by mass-spectrometry revealed Integrin Beta-1 (ITGB1) and Protein Kinase C Delta (PRKCD) as direct molecular and functional partners of CEACAM6 in supporting GBC cell migration through regulation of ERK and AKT downstream target genes MMP13, MMP14, and OCLN. Conversely, CEACAM6 knockdown abolished GBC aggressiveness, and treatment using AKT inhibitor Capivasertib and ERK inhibitor Ulixertinib counter-acted the CEACAM6-induced migration.These findings demonstrate that CEACAM6 is crucial for gallbladder oncogenesis through ERK and AKT signaling, providing insights into the design of therapeutic strategies for GBC.
2024-10-30 | GSE243305 | GEO
Project description:Purpose Gallbladder cancer (GBC) is a highly malignant tumor with extremely poor prognosis. Previous studies have suggested that the carcinogenesis and progression of GBC is a multi-stage and multi-step process, but most of them focused on the genome changes. And a few studies just compared the transcriptome differences between tumor tissues and adjacent noncancerous tissues. The transcriptome changes, relating to every stage of GBC evolution, have rarely been studied. Methods We selected three cases of normal gallbladder, four cases of gallbladder with chronic inflammation induced by gallstones, five cases of early GBC, and five cases of advanced GBC, using next-generation RNA sequencing to reveal the changes in mRNAs and lncRNAs expression during the evolution of GBC. Results In-depth analysis of the sequencing data indicated that transcriptome changes from normal gallbladder to gallbladder with chronic inflammation were distinctly related to inflammation, lipid metabolism, and sex hormone metabolism; transcriptome changes from gallbladder with chronic inflammation to early GBC were distinctly related to immune activities and connection between cells; and the transcriptome changes from early GBC to advanced GBC were distinctly related to transmembrane transport of substances and migration of cells. Conclusion Expression profiles of mRNAs and lncRNAs change significantly during the evolution of GBC, in which lipid-based metabolic abnormalities play an important promotive role, inflammation and immune activities play a key role, and changes in membrane proteins are the most highlighted molecular changes.
2022-05-31 | GSE202479 | GEO
Project description:Gallbladder carcinoma (GBC) is a rare cancer entity in Western Europe and the US with an incidence of less than 3/100.000 and a survival rate <10%. Radical surgery is the only potentially curative treatment option but most patients diagnosed with GBC are not resectable. Thus, there is a great need for the development of new treatment options, including targeted therapy for GBC. To dissect the epigenetic regulation during GBC development, we performed global miRNA profiling of 40 GBC and 8 normal gallbladder tissues. MiRNAs that are associated with survival were functionally analysed by cell proliferation and colony formation assays. In addition, we performed whole genome gene expression analysis of cells expressing miRNA mimics or control and performed biochemical assays to dissect miR-145 signalling. The GBC miRNA profiles exhibited large differences compared to normal gallbladder tissues with 49% of miRNAs being differentially expressed (FDR<0.001). In addition, 8 miRNAs were found to be down- and 16 to be up regulated in the GBCs with poor outcome (p<0.05). The most down regulated miRNA was miR-145-5p and the top up regulated miRNA was miR-575. Overexpression of miR-145 led to a significant reduction of cell proliferation and colony formation, whereas, opposite effects were observed for miR-575. Gene expression profiling of cells overexpressing miR-145 revealed activation of the STAT1 signalling pathway by inhibition of PTPRF in cholangiocellular but not hepatocellular carcinoma cells. Thereby, PTPRF directly bound to STAT1 and reduced STAT1 phosphorylation. This study identified pro- and anti-tumorigenic miRNAs in GBC and provides new mechanistic insight in the tumour suppressive function of miR-145 loss leading to active STAT1 signalling.
2017-09-23 | GSE104165 | GEO
Project description:GBC is the most common type of biliary tract cancers and the seventh most common gastrointestinal cancer. Most patients are diagnosed as GBC in an unresectable stage because of the silent symptoms. Even after curative surgery, most patients undergo recurrence due to the early metastasis and limited adjuvant therapies. All these reasons lead to an extremely dismal prognosis of advanced GBC, with a 5-year survival rate approximately 5%-10%. Cholestasis has been shown to be an important factor in the malignant progression of gallbladder cancer. In this study, we stimulate GBC-SD cells with high concentration of CDCA to simulate cholestasis and analyzed the DEGs in the stimulation of CDCA.
2023-07-07 | GSE154801 | GEO
Project description:Treatment options for advanced gallbladder cancer (GBC) are scarce and usually rely on cytotoxic chemotherapy, but unfortunately the effectiveness of any regimen is limited, and recurrence rates are high. Here, we established and characterized two gemcitabine-resistant GBC cell sublines (NOZ GemR and TGBC1 GemR) to investigate the molecular mechanisms associated with acquired resistance in vitro. The transcriptome profiling of parental and gemcitabine resistant cells revealed differential expression of multiple protein-coding genes and enrichment of biological processes such as epithelial-to-mesenchymal transition and drug metabolism. On the other hand, quantitative phosphotyrosine proteomic analysis of NOZ GemR identified aberrantly dysregulated signaling pathways in resistant cells as well as active kinases, such as Abl, PDGFRA, EphB2 and members of the Src-family that could be novel therapeutic targets against drug resistance in GBC. In line with this, NOZ GemR cells showed increased sensitivity toward the multikinase inhibitor dasatinib compared with parental cells. In conclusion, our study describes transcriptome changes and altered signaling pathways occurring in gemcitabine-resistant gallbladder cancer cells, which greatly expands our understanding of the underlying mechanisms of acquired drug-resistance in GBC. Moreover, this new gemcitabine resistant GBC models could be exploited either to study alternative mechanisms of resistance or to explore new therapies for chemotherapy-refractory GBC.
2023-05-03 | PXD036348 | Pride
Project description:Gallbladder cancer (GBC) is associated with poor disease prognosis with a survival of less than 5 years in 90% the cases. This has been attributed to late presentation of the disease, lack of early diagnostic markers and limited efficiency of therapeutic interventions. Elucidation of the molecular events in GBC carcinogenesis can contribute in better management of the disease by aiding in identification of therapeutic targets. To identify the aberrantly activated signaling events in GBC, tandem mass tag-based quantitative phosphoproteomic analysis of five GBC cell lines based on the invasive property was carried out. Using a panel of five GBC cell lines, a total of 2,623 phosphosites from 1,343 proteins were identified. Of these, 55 phosphosites were hyperphosphorylated and 39 phosphosites were hypophosphorylated in both replicates and all the 4 invasive GBC cell lines. Proline-rich Akt substrate 40 kDa (PRAS40) was one of the proteins found to be hyperphosphorylated in all the invasive GBC cell lines. Tissue microarray-based immunohistochemical labeling of phospho-PRAS40 (T246) revealed moderate to strong staining in 77% of the primary gallbladder adenocarcinoma cases. Inhibition of PRAS40 phosphorylation using inhibitors of its upstream kinases, PIM1 and AKT resulted in a significant decrease in cell proliferation, colony forming and invasive ability of the GBC cells. Our findings support the role of PRAS40 phosphorylation in tumor cell survival and aggressiveness in GBC and suggest its potential as a therapeutic target for GBC.
2019-01-28 | PXD007946 | Pride
Project description:We report here an improved protocol to reprogram mouse gallbladder cells (GBCs) into pancreatic beta cells. To fully understand the extent of reprogramming, mRNA was extracted from FACS-purified MIP-GFP positive insulin-producing cells (namely rGBC2) for RNA-seq after 10-days of in vitro reprogramming. The global gene expression profile of rGBC2 was compared with that of primary gallbladder cells, GBC reprogrammed with the rGBC1 protocol (Hickey et al., 2013) and mouse pancreatic β cells (Benner et al., 2014). We show that rGBC2 from four independent cell batches showed a unique gene expression phenotype. Compared with the rGBC1 protocol, rGBC2 expressed many additional pancreatic β cell genes, suppressed many gallbladder genes and resulted in an expression profile closer to pancreatic β cells.
2017-01-01 | GSE87606 | GEO
Project description:Gene expression signatures of highly metastatic gallbladder cancer cells
| PRJNA417578 | ENA
Project description:Gallbladder cancer (GBC) is a lethal cancer with a poor prognosis. The lack of specific and sensitive biomarkers results in delayed diagnosis with most patients presenting at late stages of the disease. Furthermore, there is little known about the molecular mechanisms associated with GBC, especially in patients of African ancestry. This study aimed to determine dysregulated proteins in South African GBC patients to identify potential mechanisms of the disease progression and plausible biomarkers. Following ethics approval, tissues (27 GBC, 13 Gall stone disease, and 5 Normal tissues) and blood plasma (53 GBC and 73 Benign biliary pathology) were obtained from consenting patients. Protein extraction was performed on all tissues and liquid chromatography-mass spectrometry was used for proteomic profiling. A project-specific spectral library was built using the Pulsar search algorithm. Principal component and Spearman’s rank correlation analyses were performed using PAST (V4.07b). Pathway and Network analyses were conducted using REACTOME v3.7 and stringAPP (v1.7.0), respectively. Levels of the liver function tests such as total bilirubin, direct bilirubin, ALP, GGT, and AST were significantly elevated (p<0.05) in patients with GBC compared to other benign pathologies including gallstone disease. In the tissue sample comparisons, there were 63 and 199 dysregulated proteins in GBC compared to normal and gallstone, respectively. In the plasma comparison, there were 34 altered proteins in GBC compared to the benign biliary pathology group. Pathway analysis showed that the dysregulated proteins in GBC patients were enriched in pathways involved in smooth muscle contraction, metabolism, ECM organization, and integrin cell surface interactions. The identified proteins help in understanding GBC molecular mechanisms in our patient group. Furthermore, the alteration of specific proteins in both tissue and protein samples suggests their potential utility as biomarkers of GBC in this sample cohort
2023-03-11 | PXD029877 | Pride