Driver Gene Alterations in Malignant Progression of Gastric Cancer
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ABSTRACT:
SUBMITTER: Dong Y
PROVIDER: S-EPMC9315095 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GIST), but insufficient for their malignant progression. Herein, we aimed to identify driver genes and signaling pathways relevant to GIST progression. We investigated genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, and gene expression for 65 clinical specimens of surgically dissected GIST, consisting of six metastatic tumors and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations included oncogenic mutations and amplification-dependent expression enhancement for oncogenes (OG), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSG). We assigned activated OG and inactivated TSG to 27 signaling pathways, the activation of which was compared between malignant GIST (metastasis and high-risk GIST) and less malignant GIST (low- and very low-risk GIST). Integrative molecular profiling indicated that a greater incidence of genetic alterations of driver genes was detected in malignant GIST (96%, 22 of 23) than in less malignant GIST (73%, 24 of 33). Malignant GIST samples groups showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and the cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K-related genes, the expression of which was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GIST. Based on our observations, we propose that inhibition of PI3K pathway signals might potentially be an effective therapeutic strategy against malignant progression of GIST.
| S-EPMC6890443 | biostudies-literature
Project description:Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GISTs), but insufficient for their malignant progression. Here, we explored to identify driver genes and signaling pathways relevant to GIST progression. We investigated gene expression along with genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, for 65 clinical specimens of surgically dissected GISTs, consisting of 6 metastasis and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations include oncogenic mutations and amplification-dependent expression enhancement for oncogenes (OGs), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSGs). We assigned activated OGs and inactivated TSGs to 27 signaling pathways, whose activation was compared between malignant GISTs (metastasis and high-risk GISTs) and less malignant GISTs (low- and very low-risk GISTs). Integrative molecular profiling indicated that higher incidence of genetic alterations of driver genes were detected more in malignant GISTs (96%, 22 of 23) than in less malignant GISTs (73%, 24 of 33). The malignant GIST samples showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K-related genes, whose expression was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GISTs. Based on our observations, we propose that inhibition of PI3K pathway signals might potentially be an effective therapeutic strategy against malignant progression of GISTs.
2019-12-04 | GSE136755 | GEO
Project description:ObjectivemiR-215 was reported to be downregulated and functioned as a tumor suppressor in several cancers. In contrast, miR-215 was preferentially upregulated in gastric cancer (GC) according to our data. Thus, we studied the potential biological function of miR-215 in GC.MethodsmiR-215 expression was measured in 77 paired GC tissues and adjacent non-tumor tissues. Biological functions of miR-215 were analyzed using cell viability, colony formation, migration, invasion, cell cycle, apoptosis and luciferase assays as well as via tumorigenicity and metastasis analysis.ResultsmiR-215 was significantly upregulated in 7 GC cell lines and 77 GC tissues compared to adjacent non-tumor tissues (P < 0.05), and miR-215 expression was greater in advanced GC (stage III/IV; P < 0.05). Ectopic expression of miR-215 in GES-1 and HGC-27 cells (low miR-215 expression) promoted cell growth, migration, invasion, and metastasis, and these were reversed in NCI-N87 cells (high miR-215 expression) after miR-215 downregulation. Potential target genes of miR-215 were predicted and RUNX1, a transcription factor and a tumor suppressor, was confirmed to be potential target according to luciferase studies. RUNX1 was downregulated in GC tissues compared to adjacent non-tumor tissues (P < 0.05), and RUNX1 reversed partial function of miR-215 in vitro.ConclusionsmiR-215 promotes malignant progression of GC by targeting RUNX1, and RUNX1 can partially reverse miR-215 effects.
| S-EPMC4826245 | biostudies-literature
Project description:The serine protease inhibitor clade E member 1 (SERPINE1) is a major inhibitor of tissue plasminogen activator and urokinase, and has been implicated in the development and progression of a variety of tumors. In this study, mRNA microarray and TCGA database were used to comprehensively analyze the upregulation of SERPINE1 in gastric cancer (GC) tissues compared with the normal stomach tissues. Kaplan-Meier results confirmed that patients with high SERPINE1 expression exhibited worse overall survival and disease-free survival. In addition, cell proliferation, cell scratches, transwell migration and invasion assay showed that SERPINE1 knockdown inhibited the proliferation, migration and invasion of GC ells. Western blot showed that the expression of VEGF and IL-6 was significantly upregulated after overexpression of SERPINE1. Meanwhile, SERPINE1 was positively correlated with the level of immune infiltration using the online analysis tools TISIDB and TIMER. And SERPINE1 expression increased with the increase of malignancy of GC which were detected by Immunohistochemistry. Finally, tumorigenesis experiments in nude mice further demonstrated that SERPINE1 could promote the occurrence and development of GC, while deletion of SERPINE1 inhibited the progression of GC. In summary, SERPINE1 was highly expressed in GC tissues, and SERPINE1 was helpful for differential diagnosis of pathological grade of gastric mucosal lesions. SERPINE1 might regulate the expression of VEGF and IL-6 through the VEGF signaling pathway and JAK-STAT3 inflammatory signaling pathway, thus ultimately affecting the invasion and migration of GC cells.
| S-EPMC8817868 | biostudies-literature
Project description:BackgroundColorectal cancer (CRC) development is generally accepted as a sequential process, with genetic mutations determining phenotypic tumor progression. However, matching genetic profiles with histological transition requires the analyses of temporal samples from the same patient at key stages of progression.ResultsHere, we compared the genetic profiles of 34 early carcinomas with their respective adenomatous precursors to assess timing and heterogeneity of driver alterations accompanying the switch from benign adenoma to malignant carcinoma. In almost half of the cases, driver mutations specific to the carcinoma stage were not observed. In samples where carcinoma-specific alterations were present, TP53 mutations and chromosome 20 copy gains commonly accompanied the switch from adenomatous tissue to carcinoma. Remarkably, 40% and 50% of high-grade adenomas shared TP53 mutations and chromosome 20 gains, respectively, with their matched carcinomas. In addition, multi-regional analyses revealed greater heterogeneity of driver mutations in adenomas compared to their matched carcinomas.ConclusionGenetic alterations in TP53 and chromosome 20 occur at the earliest histological stage in colorectal carcinomas (pTis and pT1). However, high-grade adenomas can share these alterations despite their histological distinction. Based on the well-defined sequence of CRC development, we suggest that the timing of genetic changes during neoplastic progression is frequently uncoupled from histological progression.
| S-EPMC7487684 | biostudies-literature
Project description:BackgroundEarly detection of gastric cancer (GC) remains challenging. We aimed to examine urine proteomic signatures and identify protein biomarkers that predict the progression of gastric lesions and risk of GC.MethodsA case-control study was initially designed, covering subjects with GC and gastric lesions of different stages. Subjects were aged 40-69 years, without prior diagnosis of renal or urological diseases. We enrolled a total of 255 subjects, with 123 in the discovery stage from Linqu, China, a high-risk area for GC and 132 in the validation stage from Linqu and Beijing. A prospective study was further designed for a subset of 60 subjects with gastric lesions, which were followed for 297-857 days.FindingsWe identified 43 differentially expressed urine proteins in subjects with GC vs. mild or advanced gastric lesions. Baseline urinary levels of ANXA11, CDC42, NAPA and SLC25A4 were further positively associated with risk of gastric lesion progression. Three of them, except for SLC25A4, also had higher expression in GC than non-GC tissues. Integrating these four proteins showed outstanding performance in predicting the progression of gastric lesions (AUC (95% CI): 0.92 (0.83-1.00)) and risk of GC (AUC (95% CI): 0.81 (0.73-0.89) and 0.84 (0.77-0.92) for GC vs. mild or advanced gastric lesions respectively).InterpretationThis study revealed distinct urine proteomic profiles and a panel of proteins that may predict the progression of gastric lesions and risk of GC. These biomarkers in a non-invasive approach may have translational significance for defining high-risk populations of GC and its early detection.FundingFunders are listed in the Acknowledgement.
| S-EPMC9649370 | biostudies-literature
Project description:Background: Cancer-associated fibroblasts (CAFs) are principal constituents of the tumor microenvironment (TME) and play a critical role in tumor progression. The CXCL12/CXCR4 axis regulates multiple facets of the TME. The aim of this study was to determine the relationship between CXCL12 expression in CAFs and the malignant progression of gastric cancer (GC). Methods: In the GEO (Gene Expression Omnibus) database, we performed transcriptome analysis on paired gastric cancer RNA sequencing samples, and scRNA analysis was performed on advanced malignant GC samples from the scRNA sequencing data set. Fibroblast cells were co-cultured with GC cells, and invasion, migration, epithelial-mesenchymal transformation (EMT) were determined. After blocking the expression of fibroblast CXCL12, cells were co-cultured with a GC cell line. Detection of GC cell line invasion, migration, EMT and CXCR4, Wnt5a and β-Catenin expression levels was performed. Primary CAFs and gastric normal fibroblasts were isolated and CXCL12 mRNA and protein expression were determined. In addition, a cohort of 285 GC cases was established, protein expression was evaluated immunohistochemically, and prognostic results were analyzed. Results: GC transcriptome analysis suggested that cytokine-cytokine receptor interaction and the Wnt signaling pathway in GC tissues were significantly up-regulated. scRNA analysis of advanced malignant GC samples showed that severe intestinal metaplasia (SIM) in GC specimens of different malignant grades had obvious fibroblast clusters compared to non-atrophic gastritis (NAG) and early gastric cancer (EGC). In the SIM group, fibroblast cluster, CXCL12, CXCR4, and Wnt5a were overexpressed. Co-culturing with fibroblast cells significantly increased the invasion, migration, and EMT of GC cells, and blocking CXCL12 in CAFs disturbed the expression of Wnt5a and β-catenin. In our cohort of GC patients, high CXCL12 expression in CAFs significantly correlated with histological grade (P = 0.012) and TNM stage (P = 0.014), as well as with poor overall survival (p = 0.0107). Conclusion: High expression of CXCL12 in CAFs in a GC microenvironment can affect the migration, invasion, and EMT of GC cells. Furthermore, it can cause poor prognosis in patients with GC.
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Project description:The extracellular matrix of epithelial tumors undergoes structural remodeling during periods of uncontrolled growth, creating regional heterogeneity and torsional stress. How matrix integrity is maintained in the face of dynamic biophysical forces is largely undefined. Here we investigated the role of fibulin-2, a matrix glycoprotein that functions biomechanically as an inter-molecular clasp and thereby facilitates supra-molecular assembly. Fibulin-2 was abundant in the extracellular matrix of human lung adenocarcinomas and was highly expressed in tumor cell lines derived from mice that develop metastatic lung adenocarcinoma from co-expression of mutant K-ras and p53. Loss-of-function experiments in tumor cells revealed that fibulin-2 was required for tumor cells to grow and metastasize in syngeneic mice, a surprising finding given that other intra-tumoral cell types are known to secrete fibulin-2. However, tumor cells grew and metastasized equally well in Fbln2-null and -wild-type littermates, implying that malignant progression was dependent specifically upon tumor cell-derived fibulin-2, which could not be offset by other cellular sources of fibulin-2. Fibulin-2 deficiency impaired the ability of tumor cells to migrate and invade in Boyden chambers, to create a stiff extracellular matrix in mice, to cross-link secreted collagen, and to adhere to collagen. We conclude that fibulin-2 is a driver of malignant progression in lung adenocarcinoma and plays an unexpected role in collagen cross-linking and tumor cell adherence to collagen.
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Project description:The gastrokine 1 (GKN1) protein is important for maintaining the physiological function of the gastric mucosa. GKN1 is down-regulated in gastric tumor tissues and derived cell lines and its over-expression in gastric cancer cells induces apoptosis, suggesting a possible role for the protein as a tumor suppressor. However, the mechanism by which GKN1 is inactivated in gastric cancer remains unknown. Here, we investigated the causes of GKN1 silencing to determine if epigenetic mechanisms such as histonic modification could contribute to its down-regulation. To this end, chromatin immunoprecipitation assays for the trimethylation of histone 3 at lysine 9 (H3K9triMe) and its specific histone-lysine N-methyltransferase (SUV39H1) were performed on biopsies of normal and cancerous human gastric tissues. GKN1 down-regulation in gastric cancer tissues was shown to be associated with high levels of H3K9triMe and with the recruitment of SUV39H1 to the GKN1 promoter, suggesting the presence of an epigenetic transcriptional complex that negatively regulates GKN1 expression in gastric tumors. The inhibition of histone deacetylases with trichostatin A was also shown to increase GKN1 mRNA levels. Collectively, our results indicate that complex epigenetic machinery regulates GKN1 expression at the transcriptional level, and likely at the translational level.
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Project description:Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors
| PRJNA563592 | ENA