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Expression data from gastric cancer

ABSTRACT: We used microarrays to detail the global program of gene expression between Chinese gastric cancer and its adjacent noncancer tissues and identified some key differential expression genes in cancer. Gene expression profiling is a valuable tool for identifying differentially expressed genes in studies of gastric cancer. However, it remains difficult to assign biological significance to the vast number of genes. There is an increasing awareness of gene expression profile as an important part of the contextual molecular network at play in cancer initiation and progression. The key pathways or genes might be the target for our clinical curement.

ORGANISM(S): Homo sapiens

PROVIDER: GSE19826 | GEO | 2010/01/12

SECONDARY ACCESSION(S): PRJNA122157

REPOSITORIES: GEO

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Project description:Purpose: Gastric cancer remains one of the deadliest neoplasms worldwide, with a high need for new therapeutic options. Efficacies of targeted therapies are often limited owing to the inter- and intratumoral heterogeneity of gastric cancer. Thus, drugs with broader mechanisms of action rather than relying on the inhibition of a single specific oncogene are needed. Preclinical studies have identified histone deacetylases (HDAC) and their respective isoforms as potential therapeutic targets in gastric cancer. However, clinical efficacies are moderate and the mechanism(s) of action of HDAC inhibitors (HDACi) are only partially understood. Methods: In a panel of gastric cancer cell lines with different molecular characteristics, tumor cell inhibitory effects of different HDACi were studied. Lipid peroxidation levels were measured using flow cytometry. Proteome analysis was performed for the in-depth characterization of molecular alterations upon HDAC inhibition. HDACi effects on important ferroptosis genes were validated on the mRNA (RT-qPCR) and protein level (Western Blot). Results: Upon HDACi treatment, lipid peroxidation levels were found increased in all tested cell lines. Class-I HDACi (VK1, entinostat) showed the same toxicity profile as the pan-HDACi vorinostat. Proteome analysis revealed significant and concordant alterations in the expression of proteins related to ferroptosis induction. Key enzymes like ACSL4, POR or SLC7A11 showed distinct alterations in their expression patterns, providing an explanation for the increased lipid peroxidation. Alterations of POR and SLC7A11 levels upon treatment were also confirmed in primary human gastric cancer tissue cultures as relevant ex vivo model. Conclusion: We identify the induction of ferroptosis as a new mechanism of action of class-I HDACi in gastric cancer. Notably, these findings were independent of the genetic background of the cell lines, thus introducing HDAC inhibition as a more general therapeutic principle besides other, less broadly usable targeted drugs.

Project description:In this study, the DIA proteomics technique was used to identify the protein expression in gastric adenocarcinoma and the corresponding paraneoplastic tissues, providing a rich gastric cancer protein expression dataset. Progranulin (PGRN), cyclin-dependent kinase 1 (CDK1), and occludin were selected for experimental validation in tissues and cell lines, of which PGRN has been shown to be involved in the development of cervical, rectal, bladder, bile duct, and breast cancer through various mechanisms. However, studies on the role of PGRN in gastric cancer are lacking. We investigated the function and mechanism of PGRN in gastric cancer using qRT-PCR, cell transfection, cell viability assays, cell scratch and Transwell assays, Western blot, and the establishment of a mouse tumor-bearing model in conjunction with bioinformatics and an analysis of the relationship between PGRN expression and the clinical and pathological characteristics and confirmed a high expression of PGRN in gastric cancer tissues. PGRN is also associated with gastric cancer prognosis, the degree of tumor differentiation, and lymph node metastasis. The inhibition of PGRN expression reduces cell viability, migration, and invasion, and the related genes and proteins changed accordingly. In the mouse tumor-bearing model, the tumor-forming ability of the subcutaneously transplanted tumors in nude mice was reduced after the inhibition of PGRN expression, and the genes and proteins associated with cell proliferation, migration, and invasion changed accordingly, thus confirming that PGRN promotes the invasiveness and metastasis of gastric cancer. An in-depth functional analysis of PGRN was performed using bioinformatics to predict protein interactions, miRNA regulation, and relationships with multiple immune cell types. An enrichment analysis revealed an involvement in multiple signaling pathways, and the MAPK signaling pathway was selected for validation. When PGRN expression was inhibited in the AGS and HGC27 cells, the expression of phosphorylated p38 (p-p38) in the MAPK pathway was increased, suggesting that PGRN may be involved in the development of gastric cancer by regulating p-P38 in the MAPK pathway. This study determined that there were differences in protein expression between gastric adenocarcinoma tissues and paraneoplastic tissues, and PGRN was a major differentially expressed protein involved in the proliferation, migration, and invasion of gastric cancer, indicating that it could be a potential new target gene for gastric cancer.

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Expression data from gastric cancer

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