Poor Survival In Gastric Cancer Research Articles

The prognostic importance of red blood cell distribution width for gastric cancer: a systematic review and meta-analysis.

For cancer patients, red blood cell distribution width (RDW) is a readily accessible and cost-effective preoperative prognostic predictor. This study aimed to determine whether RDW is a predictive factor for individuals undergoing radical surgery for gastric cancer (GC). A literature search was performed to select relevant studies for inclusion in the subsequent meta-analysis. Relevant data were pooled to assess the association between RDW and GC results, including overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS), as well as clinicopathological features. The meta-analysis and systemic review included data from 8 studies comprising 1,587 individuals diagnosed with GC. In this context, RDW refers to the coefficient of variation of RDW (RDW-CV). A high level of RDW-CV was significantly associated with older age [odds ratio (OR) =2.25; 95% confidence interval (CI): 1.72-2.94; P<0.00001], larger tumor diameter (OR =1.90; 95% CI: 1.42-2.56; P<0.0001), and vascular invasion (OR =2.22; 95% CI: 1.10-4.49; P=0.03). After hazard ratios (HRs) and 95% CIs were pooled, RDW-CV was found to be an independent prognostic factor of OS (HR =1.79; 95% CI: 1.21-2.66; I2=85%; P=0.004), DFS (HR =1.81; 95% CI: 1.37-2.39; I2=0%; P<0.0001), and CSS (HR =2.73; 95% CI: 1.36-5.49; I2=0%; P=0.005) in patients with GC. The association between high levels of RDW-CV and poor survival in GC suggests that RDW-CV may be a viable prognostic indicator for patients with GC.

Immunohistochemical Expression of CD90, CD133, and TPM1 in Relation to Gastric Cancer and H. pylori Association.

Gastric cancer (GC) is the second most common cause of cancer-related death worldwide. Multiple malignancies overexpress CD90, making it a helpful diagnostic and prognostic marker. CD133 is suggested to be related to poor prognosis in GC. Tropomyosin-1 (TPM1) tumor-suppressor gene low expression may predict poor survival in GC. Our study aimed to investigate CD90, CD133, and TPM1 immunohistochemical expression in GC in relation to diagnosis, prognosis, and Helicobacter pylori (H. pylori) infection. 144 paraffin blocks containing gastric cancerous (108 cases), and non-cancerous (36 cases) tissue were analyzed histopathologically for the type of lesion, grade, and stage of malignancy and by using an immunohistochemical assay for studying the expression of CD90, CD133, and TPM1. Data analysis was carried out using the Statistical Package for the Social Sciences (SPSS) version 20.0. The obtained results showed a significantly higher expression of CD90 and CD133 while showing a significantly lower expression of TPM1 in malignant samples compared to benign ones. CD90 was significantly higher in grade-3, stage-3, and N3 (p<0.05), with no significant difference concerning positive and negative H. pylori samples. CD133 percentage and H-score were significantly higher in grade-2 and stage-4 tumors than in other grades and stages, while being insignificantly higher in N3 and H. pylori-positive cases. TPM1 expression levels were significantly downregulated in GC and H. pylori-positive cases (p<0.05). TPM1 downregulation was associated with grade progression, increased depth of invasion, and tumor node metastasis. CD90, CD133, and TPM1 immunohistochemical expression in the gastric biopsy are related firmly to grades and stages of GC as well as H. pylori infection, so they could be of prognostic value. Further studies on a larger sample size are recommended.

Wnt/β-catenin signaling activation by TIMP1 confers cisplatin-resistant gastric cancer cells to malignant behaviors and epithelial–mesenchymal transition

Abstract Objectives Cisplatin (DDP) remains to be commonly employed in treating gastric cancer (GC) patients, particularly advanced-stage ones. However, acquired resistance to DDP often occurs, which causes a poor prognosis. This study aimed to understand the potential contribution of tissue inhibitor of metalloproteinase 1 (TIMP1) in acquired resistance to DDP in GC. Methods Bioinformatics analysis was performed to explore the relation of TIMP1 expression with stages and survival rate in GC. The TIMP1 expression between the parental and DDP-resistant GC cell lines were detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The effect of TIMP1 on the ability of cells against DDP was elevated by CCK-8, wounding healing, and transwell assays after exposing DDP. The role of TIMP1 in stemness and EMT process was explored through spheres formation assay and detecting stem cell- and EMT-related markers. Finally, the regulation of TIMP1 in Wnt/β-catenin signaling in DDP-resistant GC cells was also analyzed by western blot. Results Bioinformatics analysis revealed that TIMP1 is highly expressed and closely related to tumor stage and poor survival in GC. The TIMP1 expression of DDP-resistant GC cell lines was significantly higher than that of the parental one. CCK-8, wounding healing, and transwell assays showed that the tolerance to DDP of DDP-resistant AGS (AGS/DDP) cells was significantly augmented compared with that of parental AGS cells, revealed by increased IC50 and enhanced migration and invasion when exposed to DDP. Stronger stemness and epithelial–mesenchymal transition could be also observed in AGS/DDP cells. These malignant phenotypes were eliminated by silencing TIMP1 but aggravated by overexpressing TIMP1 in AGS/DDP cells. The use of the Wnt/β-catenin inhibitor could effectively reverse the function of TMIP1 overexpression in AGS/DDP cells, which suggested that the role of TIMP1 in DDP resistance relied on the Wnt/β-catenin signaling. Conclusions TIMP1 is an essential regulator of DDP resistance in GC, which may be a potential therapeutic target for cases that are refractory to DDP.

Riccardin D, a drug candidate, inhibits gastric cancer progression by targeting RAD54L

Purpose: To investigate the beneficial function of RAD54L in gastric cancer.&#x0D; Methods: Batch correction, metaboanalyst, volcano plot and heatmap were used for analyzing different expression genes. Metascape and strings were used for functional enrichment and protein-protein interaction network analysis, respectively. Expression of RAD54L was analyzed using online platform-timer, ualcan and GEPIA. Correlation between RAD54L and poor prognosis was analyzed using Kaplan-Meier curve. Expression of RAD54L was evaluated by Real Time-quantitative PCR and western blotting, while cell proliferation, cell apoptosis and cell cycle were determined by CCK8 and flow cytometry, respectively.&#x0D; Results: A total of 57 upregulated DEGs and 33 downregulated DEGs were involved in gastric cancer. Among these, RAD54L was a hub gene which is highly expressed, and is related to poor survival in gastric cancer. Moreover, knockdown of RAD54L inhibited cell viability and facilitated cell apoptosis in gastric cancer cells (p &lt; 0.05). On the other hand, overexpression of RAD54L promoted cell proliferation and reduced cell apoptosis in gastric cancer (p &lt; 0.05). In addition, RAD54L positively regulated cell cycle in gastric cancer cell lines. Furthermore, riccardin D negatively regulated cell cycle in gastric cancer cell lines by targeting RAD54L.&#x0D; Conclusion: Riccardin DRAD54L is a potential drug for the treatment of gastric cancer. However, developmental work, including in vivo studies, are required to ascertain this.

Over-expression of Anterior Gradient 3 Is Associated With Tumor Progression and Poor Survival in Gastric Cancer.

Anterior gradient (AGR) proteins, including AGR1, AGR2, and AGR3, which are members of the protein disulfide isomerase family, have been reported as biomarkers for various carcinogenesis processes. Although AGR2 and AGR1 have been demonstrated to be associated with gastric cancer (GC) progression and poor survival, the effect of AGR3 on the progression and prognosis of GC remains unknown. Therefore, our study aimed to examine the expression and prognostic significance of AGR3 in patients with GC. We investigated 271 GC patients receiving curative surgery. Formalin-fixed and paraffin-embedded tissue blocks were obtained, and long-term survival analysis was performed. The expression of AGR3 in GC tissues was investigated by quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. AGR3 was over-expressed in GC tissue compared with paired normal tissue at the mRNA and protein levels. AGR3 over-expression was significantly associated with larger tumor size, deeper tumor invasion, lymph node metastasis, and advanced tumor stage. The overall survival of patients with positive AGR3 expression was significantly lower than that of patients without positive AGR3 expression. Multivariate analysis demonstrated that AGR3 and age were independent prognostic factors associated with overall survival. Over-expression of AGR3 was significantly associated with tumor progression and poor survival of GC patients. Therefore, AGR3 may be a novel biomarker and prognostic factor for GC.

Long Noncoding RNA AP000695.2 as a Novel Prognostic Biomarker for Gastric Cancer.

Long non-coding RNA (lncRNA) AP000695.2 (ENSG00000248538) expresses abnormally in various malignancies, what shows its role as oncogene. However, it has not been extensively studied in gastric cancer. The aim of the current study was to explore the clinical value of AP000695.2 to prognose gastric cancer. The cancer genome atlas (TCGA) and the gene expression profiling interactive analysis (GEPIA) online tool were used to analyze AP000695.2 expression pattern, diagnostic and prognostic role in gastric cancer. Kaplan-Meier and Cox regression analyses were used to assess survival in patients with gastric cancer. Receiver operating curve (ROC) analysis was used to assess AP000695.2 diagnostic capacity. Nomograms were created to predict overall survival (OS) and progression free survival (PFS). LncRNA AP000695.2 was abnormally upregulated in 19 types of malignancy, including gastric cancer. Survival analysis indicated that high expression of AP000695.2 was associated with poor survival of gastric cancer. Multivariate Cox regression analysis verified the independent prognostic value of AP000695.2 to predict OS (HR (hazard ratio): 1.104, 95% CI (confidence interval): 1.035-1.178, p = 0.003) and PFS (HR: 1.170, 95% CI: 1.090-1.256, p < 0.001). ROC analysis indicated a favorable AP000695.2 diagnostic capacity (area under the curve (AUC) = 0.890). Nomograms were also constructed for OS and PFS based on AP000695.2 expression-related risk score. Additionally, AP000695.2 was found to be positively associated with tumor-infiltrating immune cells, including classically activated (M1) macrophages, neutrophils, alternatively activated (M2) macrophages, and natural killer (NK) cells. It was observed that AP000695.2 can be used as a novel biomarker to diagnose or predict survival of gastric patient.

Prognostic Value and Biological Significance of GUCY1A2 in Gastric Cancer: A Bioinformatics Analysis Base on TCGA Database

Background. Guanylate cyclase 1 soluble subunit alpha 2 (sGCα2), also known as GUCY1A2, was reported to be upregulated and promoted tumorigenesis in cervical cancer. But whether GUCY1A2 was abnormally expressed and its prognostic value in gastric cancer was unknown. The current study aimed to find out the prognostic value of GUCY1A2 in gastric cancer by analyzing data from The Cancer Genome Atlas (TCGA) database. Methods. Wilcoxon signed-rank test, cox regression analysis and multivariant analysis were used to analyze the relationship between clinical characteristic and GUCY1A2 expression level. Kaplan-Meier method was used to analyze the association of GUCY1A2 and overall survival. Gene set enrichment analysis (GSEA) was used to identify GUCY1A2-related signaling pathway. Results. Compared to normal tissue, expression of GUCY1A2 was significantly increased in gastric cancer (p&lt;0.001). Increased GUCY1A2 was associated with advanced T stage (p=0.012) and poor survival (p=0.022). Univariate analysis showed that high GUCY1A2 expression was associated with a poor overall survival (HR:1.44, 95% confidence interval [CI]: 1.03-2.02, p=0.03). Multivariate analysis indicated that GUCY1A3 remained an independent prognostic predictor of overall survival (HR:1.75, 95% confidence interval [CI]: 1.20-2.56, p=0.00). GSEA revealed that calcium signaling pathway, MAPK signaling pathway, TGF-β signaling pathway and Wnt signaling pathway were enriched in GUCY1A2 high expression phenotype. Conclusions. GUCY1A2 maybe a potential prognostic predictor of poor survival in gastric cancer. But it need to be further validated clinically.

RPP30 is a novel diagnostic and prognostic biomarker for gastric cancer.

Objective: This study aimed to identify the hub gene in gastric cancer (GC) tumorigenesis. A biomarker prediction model was constructed and analyzed, and protein expression in histopathological samples was verified in a validation cohort. Methods: Differentially expressed genes (DEGs) were identified from GC projects in The Cancer Genome Atlas (TCGA) database. Functional enrichment analysis of DEGs was performed between the high- and low- Ribonuclease P protein subunit p30 (RPP30) expression groups. ROC analysis was performed to assess RPP30 expression to discriminate GC from normal tissues. Functional enrichment pathways and immune infiltration of DEGs were analyzed using GSEA and ssGSEA. Survival analysis and nomogram construction were performed to predict patient survival. Immunohistochemical staining of GC tissues was performed to validate RPP30 expression in GC and paracancerous samples. Results: Gene expression data and clinical information of 380 cases (375 GC samples and 32 para-cancerous tissues) were collected from TCGA database. The AUC for RPP30 expression was found to be 0.785. The G alpha S signaling pathway was the most significantly enriched signaling pathway. Primary therapy outcome (p < 0.001, HR = 0.243, 95% CI = 0.156–0.379), age (p = 0.012, HR = 1.748, 95% CI = 1.133–2.698), and RPP30 expression (p < 0.001, HR = 2.069, 95% CI = 1.346–3.181) were identified as independent prognostic factors. As a quantitative approach, a nomogram constructed based on RPP30 expression, age, and primary therapy outcome performed well in predicting patient survival. Nineteen of the 25 tissue samples from the validation cohort showed positive RPP30 expression in GC tissues, whereas 16 cases showed negative RPP30 staining in normal tissues. The difference between the two was statistically significant. Conclusion: High RPP30 expression was significantly correlated with disease progression and poor survival in GC, promoting tumorigenesis and angiogenesis via tRNA dysregulation. This study provides new and promising insights into the molecular pathogenesis of tRNA in GC.

Construction of ovarian metastasis-related immune signature predicting prognosis of gastric cancer patients.

Ovarian metastasis (OM) results in poor survival of gastric cancer (GC) patients. While immunotherapy has emerged as a promising approach for late-stage GC, validated immune-related prognostic signatures still remain in need. In this study, we constructed an ovarian metastasis- and immune-related prognostic signature (OMIRPS), characterized the molecular and immune features of OMIRPS-categorized subgroups and predicted their potential response to immunotherapy. Three individual cohorts were used to construct and evaluate OMIRPS: RNA-seq of matched primary GC and OM from Fudan University Shanghai Cancer Center (FUSCC) (discovery cohort, n=4), The Cancer Genome Atlas (TCGA) (training cohort, n=544) and GSE84437 (validation cohort, n=433). Differentially expressed genes (DEGs) identified between primary GC and OM and immune-related genes (IRGs) from the ImmPort and InnateDB databases were used to identify immune-related prognostic hub genes, which were further used to construct OMIRPS by using LASSO regression analysis. Prognosis, molecular characteristics, immune features, and differential immunotherapy efficacy between different OMIRPS subgroups were analyzed. Functional analyses of DEGs revealed the significance of immune-related signatures and pathways in the OM. Immune-related prognostic hub genes including TNFRSF18, CARD11, BCL11B, NRP1, BNIP3L, and ATF3 were utilized to construct OMIRPS, which was identified as an independent prognostic factor. Comprehensive analyses unveiled the distinctive molecular and immune characteristics of OMIRPS-high and -low subgroup in regard to enriched pathways, mutation rate, tumor mutation burden, microsatellite instability status, infiltrated immune cell, immune exclusion score, andthe prediction ofimmunotherapy efficacy. Additionally, OMIRPS was associated with Immune Subtypes with borderline significance. RNA-seq of paired primary and ovarian metastatic tumors unveiled the significance of immune-related pathways and tumor immune microenvironment in OM. OMIRPS served as a promising biomarker to predict the prognosis of GC patients and distinguish the molecular features, immune characteristics, and efficacy of immunotherapy between different subgroups.

High GP73 Expression Correlates with Poor Response to Neoadjuvant Chemotherapy and Survival in Gastric Cancer: A Tissue Microarray Study.

Golgi protein 73 (GP73) is a type II Golgi transmembrane protein which is overexpressed in several cancers, however, its role in gastric cancer is still unclear. The aim of this study is to investigate if high GP73 expression is associated with pathological tumor response to neoadjuvant chemotherapy and prognosis for patients with gastric cancer. A total of 348 patients with gastric cancer, who had undergone surgery between 1999 and 2011 were retrospectively reviewed, GP73 expression was examined in tumor tissues using tissue microarray and the correlations between its expression and pathological response to neoadjuvant chemotherapy as well as patients prognosis were analyzed. We found that GP73 expression was not associated with clinicopathologic features including tumor size, differentiation and TNM stage. High expression of GP73 was associated with less pathological tumor response to neoadjuvant chemotherapy and poor survival in gastric cancer, multivariate analysis showed GP73 expression was an independent predictive factor for pathological response to neoadjuvant chemotherapy and for prognosis in patients with gastric cancer. Our results suggest that GP73 expression correlates with the effect of neoadjuvant chemotherapy and is a promising biomarker to identify patients with poor prognosis.

Progressive and Prognostic Performance of an Extracellular Matrix-Receptor Interaction Signature in Gastric Cancer.

The role of an extracellular matrix- (ECM-) receptor interaction signature has not been fully clarified in gastric cancer. This study performed comprehensive analyses on the differentially expressed ECM-related genes, clinicopathologic features, and prognostic application in gastric cancer. The differentially expressed genes between tumorous and matched normal tissues in The Cancer Genome Atlas (TCGA) and validation cohorts were identified by a paired t-test. Consensus clusters were built to find the correlation between clinicopathologic features and subclusters. Then, the least absolute shrinkage and selection operator (lasso) method was used to construct a risk score model. Correlation analyses were made to reveal the relation between risk score-stratified subgroups and clinicopathologic features or significant signatures. In TCGA (26 pairs) and validation cohort (134 pairs), 25 ECM-related genes were significantly highly expressed and 11 genes were downexpressed in gastric cancer. ECM-based subclusters were slightly related to clinicopathologic features. We constructed a risk score model = 0.081∗log2 (CD36) + 0.043∗log2 (COL5A2) + 0.001∗log2 (ITGB5) + 0.039∗log2 (SDC2) + 0.135∗log2 (SV2B) + 0.012∗log2 (THBS1) + 0.068∗log2 (VTN) + 0.023∗log2 (VWF). The risk score model could well predict the outcome of patients with gastric cancer in both training (n = 351, HR: 1.807, 95% CI: 1.292-2.528, P = 0.00046) and validation (n = 300, HR: 1.866, 95% CI: 1.347-2.584, P = 0.00014) cohorts. Besides, risk score-based subgroups were associated with angiogenesis, cell adhesion molecules, complement and coagulation cascades, TGF-beta signaling, and mismatch repair-relevant signatures (P < 0.0001). By univariate (1.845, 95% CI: 1.382-2.462, P < 0.001) and multivariate (1.756, 95% CI: 1.284-2.402, P < 0.001) analyses, we regarded the risk score as an independent risk factor in gastric cancer. Our findings revealed that ECM compositions became accomplices in the tumorigenesis, progression, and poor survival of gastric cancer.

Combining the Fibrinogen-to-Pre-Albumin Ratio and Prognostic Nutritional Index (FPR-PNI) Predicts the Survival in Elderly Gastric Cancer Patients After Gastrectomy.

BackgroundInflammation and nutrition are important causes contributing to the progression and poor survival of gastric cancer (GC). The objective of this study is to investigate the prognostic significance of the preoperative fibrinogen-to-pre-albumin ratio (FPR) and the prognostic nutritional index (PNI) in GC patients who have undergone gastrectomy.MethodsA total of 274 patients with resected pathological GC from January 2007 to December 2013 were enrolled in this retrospective study. Survival analysis was performed using Kaplan–Meier and log rank tests. Univariate and multivariate analyses were established to identify independent prognostic factors of 5-year survival. A predictive nomogram was used to predict prognosis of overall survival (OS), and its accuracy was determined by Harrell’s concordance index (C index).ResultsA high preoperative FPR-PNI score was significantly correlated with age, bigger tumor size, more lymphatic metastases and advanced TNM stage. Univariate analysis revealed that the GC patients with high FPR, low PNI and high FPR-PNI scores had shorter survival time. Multivariate analysis showed that FPR-PNI was an independent prognostic factor for OS in GC patients, especially in elderly patients. In the sub-analysis by age, the FPR-PNI score could significantly increase the accuracy of prognosis compared with the FPR and PNI alone in elderly GC patients.ConclusionThe preoperative FPR-PNI score is an effective independent prognostic index for GC patients after surgery, especially in elderly patients.

Exosome-transmitted lncRNA PCGEM1 promotes invasive and metastasis in gastric cancer by maintaining the stability of SNAI1.

Clinically, hypoxia is associated with increased distant metastasis and poor survival in gastric cancer (GC). In this study, we set out from the cellular interaction to further explain the molecular mechanism of invasion in GC cells under hypoxic conditions. Gastric cancer cells were cultured under 1% O2 (hypoxia-cultured gastric cancer cells, HGC) and 20% O2 condition (normoxic-cultured gastric cancer cells, NGC). NGC was co-cultured with HGC-medium. Scrape and Transwell were used to evaluate invasion and migration. Exosomes from GC were extracted by ultracentrifugation. Electron microscopy images, western-blot used to analyze the size distributions and the number of exosomes. HGC-medium induced NGC dissociated. Long non-coding RNA (lncRNA) prostate cancer gene expression marker 1 (PCGEM1) was specifically expressed in HGC exosomes. HGC-derived PCGEM1-riched exosomes could promote the invasion and migration of NGC. On the mechanism, PCGEM1 maintained stability and reduced the degradation of SNAI1, which could induce the epithelial-mesenchymal transition of GC. LncRNA PCGEM1 was overexpressed in GC cells. And part of the PCGEM1 can be encapsulated into exosomes. These exosomes promoted invasion and migration of other GC cells. We considered PCGEM1 might act as a "scaffold" combined with SNAI1 and prompt the invasion and migration of GC.

Molecular landscape of gastric cancer (GC) harboring mutations of histone methyltransferases.

418 Background: Alteration of histone modifications participating in transcription and genomic instability, has been recognized as an important role in tumorigenesis. Aberrant expression of histone-lysine N-methyltransferase 2 ( KMT2) family, which methylate histone H3 on lysine 4, is significantly correlated with poor survival in GC. Understanding how gene mutations of KMT2 family interact to affect cancer progression could lead to new treatment strategies. Methods: A total of 1,245 GC were analyzed using next-generation sequencing (NGS) and immunohistochemistry (IHC; Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutations, and MSI status was evaluated by a combination of IHC, fragment analysis and NGS. PD-L1 status was analyzed by IHC (SP142). Gene fusions were detected by Archer (N = 59) or whole-transcriptome sequencing (N = 129). Results: The overall mutation rate of genes in KMT2 family was 10.6% ( KMT2A: 1.7 %, KMT2C: 4.7%, KMT2D: 7.1%). Overall, the mutation rates were significantly higher in KMT2-mutated (MT) GC than KMT2-wild type (WT) GC, except for TP53 (43% vs 63%, p &lt; .0001). Interestingly, among the genes with significant higher mutation rates in KMT2-MT GC, 28% (21/76) of them were related to DNA damage repair (including BRCA1/ 2, RAD50) and 33% (25/76) of them were related to chromatin remodeling (including ARID1A/ 2, SMARCA4). Overexpression of HER2, amplifications of KRAS, CDK6 and HER2 were significant lower, while PCM1 and BCL3 amplifications were significant higher in KMT2-MT, compared to KMT2-WT GC ( p &lt; .05). Significantly higher prevalence of TMB-high ( &gt; 17mut/MB) (49% vs 3%), MSI-H (53% vs 2%), and PD-L1 overexpression (20% vs 7%) were present in KMT2-MT GC, compared to KMT2-WT GC ( p &lt; .001). The rates of fusions involving ARHGAP26 (19% vs 3%, p &lt; .01)and RELA (29% vs 0%, p &lt; .0001) were significantly higher in KMT2-MT than those in KMT2-WT GC. Conclusions: This is the largest study to investigate the distinct genomic landscape between KMT2-MT and WT GC. Our data indicates that KMT2-MT GC patients could potentially benefit from agents targeting DNA damage repair and immunotherapy, which warrants further in-vitro and in-vivo investigation.

CircDUSP16 promotes the tumorigenesis and invasion of gastric cancer by sponging miR-145-5p

BackgroundCircular RNAs (circRNAs) as a novel subgroup of non-coding RNAs act a critical role in the pathogenesis of gastric cancer (GC). However, the underlying mechanisms by which hsa_circ_0003855 (circDUSP16) contributes to GC are still undocumented.MaterialsThe differentially expressed circRNAs were identified by GEO database. The association of circDUSP16 or miR-145-5p expression with clinicopathological features and prognosis in GC patients was analyzed by FISH and TCGA-seq data set. Loss- and gain-of-function experiments as well as a xenograft tumor model were performed to assess the role of circDUSP16 in GC cells. circDUSP16-specific binding with miR-145-5p was confirmed by bioinformatic analysis, luciferase reporter, and RNA immunoprecipitation assays.ResultsThe expression levels of circDUSP16 were markedly increased in GC tissue samples and acted as an independent prognostic factor of poor survival in patients with GC. Knockdown of circDUSP16 repressed the cell viability, colony formation, and invasive potential in vitro and in vivo, but ectopic expression of circDUSP16 reversed these effects. Moreover, circDUSP16 possessed a co-localization with miR-145-5p in the cytoplasm, and acted as a sponge of miR-145-5p, which attenuated circDUSP16-induced tumor-promoting effects and IVNS1ABP expression in GC cells. MiR-145-5p had a negative correlation with circDUSP16 expression and its low expression was associated with poor survival in GC patients.ConclusionsCircDUSP16 facilitates the tumorigenesis and invasion of GC cells by sponging miR-145-5p, and may provide a novel therapeutic target for GC.

Exosomal miR-196a-1 promotes gastric cancer cell invasion and metastasis by targeting SFRP1.

Aim: To investigate the role of exosomal miRNAs on gastric cancer (GC) metastasis. Materials & methods: miRNA expression profiles of exosomes with distinct invasion potentials were analyzed using miRNA microarray and validated by quantitative real-time PCR. In vitro and in vivo experiments assessed the role of exosomal miR-196a-1 in GC's metastasis. Results: High expression level of exosomal miR-196a-1 expression was significantly associated with poor survival in GC. Exosomes that contained miR-196a-1 were secreted from high-invasive GC cells. Ectopic miR-196a-1 expression promoted invasion of low-invasive GC cells by targeting SFRP1. Conclusion: miR-196a-1 was delivered from high-invasive GC into low-invasive GC cells via exosomes and promoted metastasis to the liver in vitro and in vivo.

Comprehensive analysis of histone modification-associated genes on differential gene expression and prognosis in gastric cancer.

Accumulating evidence suggests that the epigenetic alterations caused by histone modifications have important roles in the genesis of gastric cancer (GC), particularly the well-studied acetylation and methylation modifications. In the present study, a Bioinformatics analysis of the expression of histone modification-associated genes in GC and normal tissues was performed by using datasets from Oncomine, the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). The clinical data of GC patients were downloaded from TCGA to determine the association between histone modification-associated gene expression and clinicopathological parameters or survival of GC. Finally, lysine acetyltransferase 2A (KAT2A), nuclear receptor coactivator 1 (NCOA1), SMYD family member 5 (SMYD5), protein arginine methyltransferase 1 (PRMT1) and PRDF1-RIZ (PR)/Su(var)3-9, enhancer-of-zeste and trithorax (SET) domain 16 (PRDM16) were screened; KAT2A, SMYD5 and PRMT1 were upregulated, while PRDM16 expression was downregulated in GC. Analysis of the GEO and Oncomine datasets revealed that NCOA1 was upregulated, which was contrary to the result obtained with the TCGA stomach adenocarcinoma dataset. Aberrant expression of KAT2A, NCOA1, SMYD5 and PRMT1 was more obvious in gastric intestinal-type adenocarcinoma; low NCOA1 expression was associated with better overall survival of GC patients [hazard ratio (HR)=0.690, 95% CI=0.570-0.840, P<0.001] and was an independent predictor for patients diagnosed with GC (HR=0.639, 95% CI=0.437-0.933, P=0.020). Correlation analysis and protein-protein interaction network analysis indicated a close association between ATAD2 and estrogen receptor 1 (ESR1), PRMT1, NCOA1 and KAT2A. In conclusion, differential expression of KAT2A, NCOA1, SMYD5, PRMT1 and PRDM16 was identified in GC vs. normal tissues, low NCOA1 expression was associated with poor survival of GC and ATAD2 may interact with ESR1 to regulate NCOA1 and PRMT1 in GC.

VEGFR2 promotes tumorigenesis and metastasis in a pro-angiogenic-independent way in gastric cancer

BackgroundVEGF/VEGFR2 pathway is the central therapeutic target in anti-angiogenic treatment in multiple cancers. However, little work has been carried out concerning the pro-malignancy functions of VEGFR2 that are independent of its pro-angiogenesis effects in gastric cancer. Here, we demonstrated that VEGFR2 up-regulation in gastric cancer tissues was a prognostic marker for poor disease-free survival and overall survival of gastric cancer patients.MethodsImmunohistochemistry was used to detect VEGFR2 and VTN expressions in specimens. Kaplan–Meier curves were constructed for survival analysis. Stably knockdown cell lines and overexpression cell lines were constructed by small interfering RNA and plasmids transfection. Real-time PCR and Western blot were used to confirm the expressions of target genes at both RNA and protein levels. Cell proliferation was measured by using Cell Counting Kit-8 and xenograft models. Microarray and bioinformatic analysis were also performed to identify the relationship between Vitronectin (VTN) and VEGFR2.ResultsWhen overexpressed in gastric cancer cells, VEGFR2 increased cellular proliferation and invasion in vitro and tumor formation in xenograft models. By using integrating microarray and bioinformatic analysis, we identifiedVTN as a downstream of VEGFR2 pathway. In gain- and loss-of function analysis in gastric cancer cells, VTN was further verified in consistent with VEGFR2 in expression levels and in regulating cell growth and motility in vitro and in vivo. Moreover, in gastric cancer samples, VTN was as also revealed as a poor prognostic factor.ConclusionsOur present findings defined a novel activity for VEGFR2 in promoting tumorogenicity, motility and indicating a poor survival in gastric cancer beyond its known pro-angiogenic effects.ImplicationsOur present findings defined a novel activity for VEGFR2 in promoting tumorogenicity, motility and indicating a poor survival in gastric cancer beyond its known pro-angiogenic effects, which may provide a new and valuable target for design of therapies for intervention and a new cognitive perspective for the anti-angiogenesis therapies.

KCND2 upregulation might be an independent indicator of poor survival in gastric cancer.

We aimed to investigate the expression of voltage-gated potassium channels KCND1/KCND2/KCND3 in gastric cancer (GC) and normal stomach tissues and to investigate the prognostic value of the upregulated gene KCND2. A retrospective analysis was performed using data from large available databases. KCND2 was significantly upregulated at the mRNA and protein levels in GC compared with that in normal stomach tissues. High KCND2 RNA expression was independently associated with shorter overall survival (HR: 1.634, 95% CI: 1.135-2.352; p=0.008) and recurrence-free survival (HR: 2.644, 95% CI: 1.438-4.863; p=0.002). Data mining in the Kaplan-Meier plotter confirmed the prognostic value of KCND2. KCND2 upregulation is a valuable prognostic biomarker in GC patients, in terms of overall survival and recurrence-free survival.

Loss of LINC01939 expression predicts progression and poor survival in gastric cancer

As highly tissue-specific genes, it is increasingly recognized that long non-coding RNAs (lncRNAs) are considered as promising prognostic biomarkers for multiple human cancers. However, lack of tissue-specific lncRNAs in gastric cancer (GC) still exist. In this study, we identified a novel lncRNA LINC01939 which showed the largest fold change in GC than other human cancers from lnCAR database by bioinformatic analysis. Reverse transcription quantitative polymerase chain reaction (qPCR) assay confirmed that LINC01939 was significantly downregulated in GC tissues compared with matched normal tissues. Low expression of LINC01939 was positively associated with advanced TNM stage and lymphatic metastasis. Patients with low LINC01939 expression have remarkably shorter overall survival (OS) and progression-free survival (PFS) than those with high LINC01939 expression. Univariate and multivariate analysis showed that LINC01939 is an independent protective predictor of OS and PFS in GC patients. Therefore, our data suggest that the newly identified lncRNA LINC01939 might act as a potential prognostic biomarker for GC.