Poor Prognosis In Gastric Adenocarcinoma Research Articles

Expression of Serpin Family E Member 1 (SERPINE1) Is Associated with Poor Prognosis of Gastric Adenocarcinoma.

The aberrant expression of serpin family E member 1 (SERPINE1) is associated with carcinogenesis. This study assessed the alteration of SERPINE1 expression for an association with gastric adenocarcinoma prognosis. The Cancer Genome Atlas (TCGA) dataset was applied to investigate the impact of SERPINE1 expression on the survival of patients afflicted with gastric cancer. Subsequently, 136 samples from the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University were subjected to qRT-PCR and Western blot to validate the expression level of SERPINE1 between tumor and adjacent normal tissues. The correlation between the expression of SERPINE1 with the clinicopathological features in TCGA patients was analyzed using Wilcoxon signed-rank and logistic regression tests. The potential molecular mechanism associated with SERPINE1 expression in gastric cancer were confirmed using gene set enrichment analysis (GSEA). The TCGA data showed that SERPINE1 was overexpressed in tumor tissues compared to normal mucosae and associated with the tumor T stage and pathological grade. SERPINE1 overexpression was associated with the poor overall survival (OS) of patients. The findings were confirmed with 136 patients, that is, SERPINE1 expression was associated with poor OS (hazard ratio (HR): 1.82; 95% confidence interval (CI): 0.84-1.83; p = 0.012)) as an independent predictor (HR: 2.11, 95% CI: 0.81-2.34; p = 0.009). The resulting data were further processed by GSEA showed that SERPINE1 overexpression was associated with the activation of EPITHELIAL_MESENCHYMAL_TRANSITION, TNFA_SIGNALING_VIA_NFKB, INFLAMMATORY_RESPONSE, ANGIOGENESIS, and HYPOXIA. SERPINE1 overexpression is associated with a poor gastric cancer prognosis.

GRK3 is a poor prognosticator and serves as a therapeutic target in advanced gastric adenocarcinoma

BackgroundG protein-coupled receptor (GPCR) is the most targeted protein family by the FDA-approved drugs. GPCR-kinase 3 (GRK3) is critical for GPCR signaling. Our genomic analysis showed that GRK3 expression correlated with poor prognosis of gastric adenocarcinoma (GAC) patients. However, GRK3’s functions and clinical utility in GAC progression and metastases are unknown.MethodsWe studied GRK3 expression in normal, primary, and metastatic GAC tissues. We identified a novel GRK3 inhibitor, LD2, through a chemical-library screen. Through genetic and pharmacologic modulations of GRK3, a series of functional and molecular studies were performed in vitro and in vivo. Impact of GRK3 on YAP1 and its targets was determined.ResultsGRK3 was overexpressed in GAC tissues compared to normal and was even higher in peritoneal metastases. Overexpression (OE) of GRK3 was significantly associated with shorter survival. Upregulation of GRK3 in GAC cells increased cell invasion, colony formation, and proportion of ALDH1+ cells, while its downregulation reduced these attributes. Further, LD2 potently and specifically inhibited GRK3, but not GRK2, a very similar kinase to GRK3. LD2 highly suppressed GAC cells’ malignant phenotypes in vitro. Mechanistically, GRK3 upregulated YAP1 in GAC tissues and its transcriptional downstream targets: SOX9, Birc5, Cyr61 and CTGF. Knockdown (KD) YAP1 rescued the phenotypes of GRK3 OE in GAC cells. GRK3 OE significantly increased tumor growth but LD2 inhibited tumor growth in the PDX model and dramatically suppressed peritoneal metastases induced by GRK3 OE.ConclusionsGRK3, a poor prognosticator for survival, conferred aggressive phenotype. Genetic silencing of GRK3 or its inhibitor LD2 blunted GRK3-conferred malignant attributes, suggesting GRK3 as a novel therapeutic target in advanced GAC.

Integrated Bioinformatics Analysis for Identifying the Significant Genes as Poor Prognostic Markers in Gastric Adenocarcinoma.

Gastric adenocarcinoma (GAC) is the most common histological type of gastric cancer and imposes a considerable health burden globally. The purpose of this study was to identify significant genes and key pathways participated in the initiation and progression of GAC. Four datasets (GSE13911, GSE19826, GSE54129, and GSE79973) including 171 GAC and 77 normal tissues from Gene Expression Omnibus (GEO) database were collected and analyzed. Through integrated bioinformatics analysis, we obtained 69 commonly differentially expressed genes (DEGs) among the four datasets, including 20 upregulated and 49 downregulated genes. The prime module in protein-protein interaction network of DEGs, including ADAMTS2, COL10A1, COL1A1, COL1A2, COL8A1, BGN, and SPP1, was enriched in protein digestion and absorption, ECM-receptor interaction, focal adhesion, PI3K-Akt signaling pathway, and amoebiasis. Furthermore, expression and survival analysis found that all seven hub genes were highly expressed in GAC tissues and 6 of them (except for SPP1) were able to predict poor prognosis of GAC. Finally, we verified the 6 high-expressed hub genes in GAC tissues via immunohistochemistry, Western blot, and RNA quantification analysis. Altogether, we identified six significantly upregulated DEGs as poor prognostic markers in GAC based on integrated bioinformatical methods, which could be potential molecular markers and therapeutic targets for GAC patients.

Comment on: Increasing frequency of gene copy number aberrations is associated with immunosuppression and predicts poor prognosis in gastric adenocarcinoma.

Comment on: Increasing frequency of gene copy number aberrations is associated with immunosuppression and predicts poor prognosis in gastric adenocarcinoma.

Author response to: Increasing frequency of gene copy number aberrations is associated with immunosuppression and predicts poor prognosis in gastric adenocarcinoma.

Author response to: Increasing frequency of gene copy number aberrations is associated with immunosuppression and predicts poor prognosis in gastric adenocarcinoma.

Protein Phosphatase PPM1B Inhibits Gastric Cancer Progression and Serves as a Favorable Prognostic Biomarker.

Protein phosphatase PPM1B, also named as PP2Cβ, is a member of serine/threonine phosphatase family. Dysregulated expression of PPM1B has been reported in several malignancies; nevertheless, its role in gastric cancer remains unknown. Here, we aimed to initially investigate the expression and function of PPM1B in gastric adenocarcinoma. We firstly evaluated the protein expression of PPM1B in our enrolled retrospective cohort (n=161) via immunohistochemistry staining. Univariate and multivariate analyses were conducted to assess its prognostic value. Cellular experiments and xenografts in mice model were also performed to validate the role of PPM1B in gastric adenocarcinoma progression. The advanced tumor stage was characterized with a lower PPM1B level. Lower PPM1B was associated with poor prognosis in both The Cancer Genome Atlas (TCGA) dataset and our cohort (P<0.05). Furthermore, Cox regression analysis demonstrated that PPM1B was a novel independent prognostic factor for gastric adenocarcinoma patients (hazard ratio=0.35, P=0.001). Finally, cellular and xenografts data confirmed that overexpressing PPM1B can remarkably attenuated gastric adenocarcinoma growth. Low expression of PPM1B may be a potential molecular marker for poor prognosis in gastric adenocarcinoma.

Increasing frequency of gene copy number aberrations is associated with immunosuppression and predicts poor prognosis in gastric adenocarcinoma.

Patients with Epstein-Barr virus-positive gastric cancers or those with microsatellite instability appear to have a favourable prognosis. However, the prognostic value of the chromosomal status (chromosome-stable (CS) versus chromosomal instable (CIN)) remains unclear in gastric cancer. Gene copy number aberrations (CNAs) were determined in 16 CIN-associated genes in a retrospective study including test and validation cohorts of patients with gastric cancer. Patients were stratified into CS (no CNA), CINlow (1-2 CNAs) or CINhigh (3 or more CNAs). The relationship between chromosomal status, clinicopathological variables, and overall survival (OS) was analysed. The relationship between chromosomal status, p53 expression, and tumour infiltrating immune cells was also assessed and validated externally. The test and validation cohorts included 206 and 748 patients, respectively. CINlow and CINhigh were seen in 35.0 and 15.0 per cent of patients, respectively, in the test cohort, and 48.5 and 20.7 per cent in the validation cohort. Patients with CINhigh gastric cancer had the poorest OS in the test and validation cohorts. In multivariable analysis, CINlow, CINhigh and pTNM stage III-IV (P < 0.001) were independently associated with poor OS. CIN was associated with high p53 expression and low immune cell infiltration. CIN may be a potential new prognostic biomarker independent of pTNM stage in gastric cancer. Patients with gastric cancer demonstrating CIN appear to be immunosuppressed, which might represent one of the underlying mechanisms explaining the poor survival and may help guide future therapeutic decisions.

CREM Is Correlated With Immune-Suppressive Microenvironment and Predicts Poor Prognosis in Gastric Adenocarcinoma.

The transcriptional repressor cAMP response element modulator (CREM) has an important role in T-cell development. In this study, we used the integrated Bioinformatics Methods to explore the role of CREM in gastric adenocarcinoma (GAC). Our results showed that high CREM expression was closely related with poorer overall survival in GAC. By GSEA cluster analysis, we found that the high expression of CREM was associated with the cancer-associated pathway in GAC. Moreover, single-cell sequencing data showed that CREM is mainly localized in exhausted CD8+ T cells. Its prognostic value and the potential function lead to T-cell exhaustion in the tumor microenvironment (TME). Similar results were also obtained in glioma and lung cancer. High expression of CREM, correlated with clinical relevance of GAC, was associated with T-cell exhaustion and M2 polarization in GAC. These findings suggest that CREM can be used as a prognostic biomarker in GAC, which might provide a novel direction to explore the pathogenesis of GAC.

Sema3C promotes hepatic metastasis and predicts poor prognosis in gastric adenocarcinoma.

ObjectiveSemaphorin 3C (Sema3C) may regulate tumor metastasis and prognosis. We determined the biological roles of Sema3C in the hepatic metastasis of gastric adenocarcinoma and evaluated its clinical significance as a potential biomarker.MethodsSema3C expression in gastric cancer (GC) cell lines and tissues was measured using RT-qPCR and western blotting. Moreover, Sema3C functions were analyzed using Transwell assays and in vitro metastasis assays in gain- and loss-of-function experiments. Furthermore, the impact of Sema3C on the prognosis of 80 randomly selected patients with GC was investigated by immunohistochemistry. Additionally, the expression of epithelial-mesenchymal transition (EMT) indicators was verified by immunohistochemistry in GC tissues.ResultsSema3C expression was significantly upregulated in highly metastatic GC cell lines and tissues. Additionally, Sema3C promoted invasion, migration and hepatic metastasis in GC cells. Moreover, Sema3C expression was positively correlated with clinicopathological features in GC and paired hepatic metastatic tissues, and Sema3C expression was an independent prognostic factor. Finally, Sema3C expression was associated with node metastasis, hepatic metastasis and EMT marker expression.ConclusionsSema3C may play roles in regulating the EMT and metastasis of gastric adenocarcinoma, highlighting its potential use as a prognostic factor for hepatic metastasis and poor prognosis in gastric adenocarcinoma.

LINC00641/miR-582-5p mediate oxaliplatin resistance by activating autophagy in gastric adenocarcinoma

The poor prognosis of gastric adenocarcinoma is partly due to chemotherapy failure, especially the oxaliplatin-based chemotherapy. However, the specific mechanism of oxaliplatin resistance is unclear. We aim to find the roles that LINC00641 and miR-582-5p play in regulating oxaliplatin resistance. Quantitative reverse transcriptase-PCR was used to evaluate the expression of LINC00641 and microRNA-582-5p (miR-582-5p) in gastric cancer both in vivo and in vitro. Transwell and CCK-8 assays were performed; and LC3 I/II and p62 were detected by western blot to evaluate the activation of autophagy. LINC00641 expression was associated with prognosis and oxaliplatin resistance in patients with gastric adenocarcinoma. The expression of LINC00641 was higher in gastric cancer tissues; whereas miR-582-5p was down-regulated in gastric cancer tissues. Moreover, LINC00641 was highly expressed in oxaliplatin-resistant cell lines and miR-582-5p was down-regulated. In addition, LINC00641 negatively regulated the expression of miR-582-5p. With regard to biological functions, down-regulation of LINC00641 suppressed cell migration and proliferation. Further experiments indicated that down-regulation of LINC00641 inhibited the autophagy process, making gastric cancer cells more sensitive to oxaliplatin. LINC00641 and miR-582-5p are biomarkers for predicting overall survival, as they were involved in regulating oxaliplatin resistance by altering autophagy in gastric adenocarcinoma.

Dissecting transcriptional heterogeneity in primary gastric adenocarcinoma by single cell RNA sequencing

ObjectiveTumour heterogeneity represents a major obstacle to accurate diagnosis and treatment in gastric adenocarcinoma (GA). Here, we report a systematic transcriptional atlas to delineate molecular and cellular heterogeneity in GA...

LETM1 is a potential biomarker that predicts poor prognosis in gastric adenocarcinoma

Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is closely linked to the occurrence and development of many malignant tumors. Many studies have reported that enhanced expression of LETM1 in several types of human cancers was associated with poor clinical outcomes; however, its clinical significance in gastric adenocarcinoma (GA) has not been elucidated. In this study, we assessed the expression of LETM1 along with the genes related to cancer stemness, cell cycle, and PI3K/Akt signaling in 189 paraffin-embedded GA tissue samples and GA-derived cell lines using immunohistochemistry (IHC), western blotting, and immunofluorescence. Our results showed that the expression of LETM1 was strongly correlated with the tumor grade, primary tumor (pT) stage, lymph node metastasis, clinical stage, and tumor gross type of GA. The Kaplan-Meier survival analysis revealed that patients with GA with high expression of LETM1 exhibit a shorter overall survival (OS) rate. Univariate and multivariate Cox regression analysis indicated that LETM1 is an independent poor prognostic factor of GA. Significantly, LETM1 expression was positively correlated with the expression of cancer stemness-related genes such as CD44 and LGR5 and expression of cell-cycle related gene, cyclin D1. Further, the expression of proteins involved in PI3K/Akt signaling pathway, such as pPI3K-p85 and pAkt-Thr308, was also increased. Additionally, small interfering RNA (esiRNA)-mediated silencing of LETM1 expression in GA-derived cell lines MKN28 and MKN74 strongly inhibited the expression of stemness and cell cycle-related proteins, suppressed cancer cell spheroid formation, migration and invasion ability, and affected cell cycle distribution. Furthermore, the GA-derived cell line AGS exhibited enhanced expression of LETM1, CD44, LGR5, and HIF1-α under hypoxic conditions. Lastly, we blocked PI3K expression using an inhibitor LY294002, which downregulated the expression of LETM1, pPI3K-p85, and pAkt-Thr308. Taken together, our results demonstrate that LETM1 regulates cell proliferation and promotes tumorigenicity of GA, and its overexpression is associated with the poor progression of GA. Therefore, LETM1 could serve as a potential prognostic biomarker and a therapeutic target for the better clinical management of GA.

FN1, SPARC, and SERPINE1 are highly expressed and significantly related to a poor prognosis of gastric adenocarcinoma revealed by microarray and bioinformatics

Gastric adenocarcinoma (GAC), also known as stomach adenocarcinoma (STAD), is one of the most lethal malignancies in the world. It is vital to classify and detect the hub genes and key pathways participated in the initiation and progression of GAC. In this study, we collected and sequenced 15 pairs of GAC tumor tissues and the adjacent normal tissues. Differentially expressed genes (DEGs) were analyzed and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) analysis were used to annotate the unique biological significance and important pathways of enriched DEGs. Moreover, we constructed the protein-protein interaction (PPI) network by Cytoscape and conducted KEGG enrichment analysis of the prime module. We further applied the TCGA database to start the survival analysis of these hub genes by Kaplan-Meier estimates. Finally, we obtained total 233 DEGs consisted of 64 up-regulated genes and 169 down-regulated genes. GO enrichment analysis found that DEGs most significantly enriched in single organism process, extracellular region, and extracellular region part. KEGG pathway enrichment analysis suggested that DEGs most significantly enriched in Protein digestion and absorption, Gastric acid secretion, and ECM-receptor interaction. Furthermore, the PPI network showed that the top 10 hub genes in GAC were IL8, COL1A1, MMP9, SST, COL1A2, TIMP1, FN1, SPARC, ALDH1A1, and SERPINE1 respectively. The prime gene interaction module in PPI network was enriched in protein digestion and absorption, ECM receptor interaction, the PI3K-Akt signaling pathway, and pathway in cancer. Survival analysis based on the TCGA database found that the expression of the FN1, SERPINE1, and SPARC significantly predicted poor prognosis of GAC. Collectively, we identified several hub genes and key pathways associated with GAC initiation and progression by analyzing the microarray data on DEGs, which provided a detailed molecular mechanism underlying GAC occurrence and progression.

MMP7 Induces T-DM1 Resistance and Leads to the Poor Prognosis of Gastric Adenocarcinoma via a DKK1-Dependent Manner.

Gastric adenocarcinoma is one of the most common and lethal cancer types and is known as the second leading cause of cancer-related death of Asian adults, early diagnosis based on either pathology or molecular biology could be one of the most efficient ways to improve the outcomes of gastric adenocarcinoma patients. Quantitative Real-Time PCR and Western-blot were used in detection of mRNA and protein expression. Lentivirus infection was used to overexpression or knock down target gene. Alarma blue assay was used to monitor cells proliferation. Flow cytometry analysis was performed to test protein expression and apoptosis level. Immunohistochemistry was used to identify protein expression in tissue. Statistical differences between two groups are evaluated by two-tailed t-tests. The comparison among multiple groups is performed by one-way Analysis of Variance (ANOVA) followed by Dunnett's posttest. The statistical significance of the Kaplan-Meier survival plot is determined by log-rank analysis. MMP7 as one of the most up-regulated genes in T-DM1 resistant NCI-N87 gastric adenocarcinoma cells compared to matched naïve cell lines. T-DM1 resistant NCI-N87 cell lines by exposed to T-DM1 in vitro. Exogenous overexpression of MMP7 promotes T-DM1 resistance and tumor growth in NCI-N87 cell lines while MMP7 knockdown enhanced sensitivity to T-DM1 in T-DM1 resistant NCI-N87 cell lines established previously. MMP7 was enriched in high WHO grade GC samples and implies poor outcomes for these patients. DKK1 as one of the most correlated genes to MMP7 in gastric adenocarcinoma and knock-down of DKK1 or inhibition of Wnt/β-catenin pathway led to a decreased expression of MMP7 and resistance to T-DM1. DKK1 and Wnt/β-catenin-dependent activation of MMP7 induces T-DM1 resistance and leads to the poor prognosis of gastric adenocarcinoma, which might be a novel potential therapeutical target for T-DM1 resistant gastric adenocarcinoma.

Reduced Expression of Deubiquitinase USP33 Is Associated with Tumor Progression and Poor Prognosis of Gastric Adenocarcinoma.

BackgroundUbiquitin-specific peptidase 33 (USP33) is a deubiquitinase that balances the ubiquitin status of proteins. It has been reported to act as a tumor suppressor in colorectal cancer and lung cancer. However, the expression pattern and clinical significance of USP33 have not been investigated in gastric adenocarcinoma (GAC).Material/MethodsWe explored the USP33 protein and RNA levels by immunohistochemistry (IHC), Western blot analysis, and qRT-PCR. The Pearson chi-square test was performed to evaluate the statistical associations between USP33 level and patient characteristics. Additionally, the relationship between USP33 expression and patient survival was investigated. Cellular studies, including proliferation assay, migration assay, and invasion assay, were conducted to demonstrate the underlying mechanisms of USP33 in GAC progression.ResultsThis study included 121 patients with GAC. USP33 showed a decreased expression in GAC tissues compared to adjacent normal gastric tissues. Low expression of USP33 was correlated with invasion depth and advanced TNM stage. According to survival analysis, upper location of tumor (P=0.003), invasion depth (P=0.048), advanced TNM stage (P=0.001), and low USP33 level (P=0.001) were all associated with poor overall survival of GAC patients. Cox analysis confirmed the independent role of USP33 in predicting patient survival. Cell experiments showed that USP33 overexpression significantly inhibited the proliferation, migration, and invasion of GAC cells.ConclusionsUSP33 was downregulated in GAC, and was an independent prognostic factor. In vitro results demonstrated the role of USP33 in suppressing tumor progression, suggesting that the developing an agonist of USP33 may be a novel direction for chemotherapy development.

ACOT1 expression is associated with poor prognosis in gastric adenocarcinoma

Acyl-CoA thioesterase 1 (ACOT1) is an important isoform of the ACOT family that catalyzes the reaction of fatty acyl-CoAs to CoA-SH and free fatty acids. Recent studies of gastrointestinal tumor metabolism suggest that there is abnormal metabolism of lipids and fatty acids during tumor progression. However, the function and contribution of ACOT1 in gastric cancer development are still poorly understood. In addition, GLI3 is a major transcription factor in the regulation of hedgehog signaling. GLI3 mutations induce glandular expansion and intestinal metaplasia in gastric cancer, which indicates a role for GLI3 in the preneoplastic process. Thus, we investigated the relationship between ACOT1 expression and GLI3 in gastric adenocarcinoma. A tissue microarray was constructed from 280 cases of gastric adenocarcinoma. The immunohistochemistry method was performed on tissue sections of 4 μm from each tissue microarray block. We found a significant correlation between ACOT1 expression and poor histologic grade, a lower T category, TNM stage, and increased GLI3 expression. In addition, the survival analysis revealed that the ACOT1-positive group had significantly decreased overall survival rates compared with the ACOT1-negative group. Furthermore, GLI3 expression had a significant positive correlation with ACOT1 expression in gastric adenocarcinoma cells. In summary, these findings demonstrate that increased expression of ACOT1 is correlated with pivotal clinicopathological parameters and poor prognosis in gastric adenocarcinoma through increased expression of the potential tumor-promoting protein GLI3.

Elevated expression of Nodal and YAP1 is associated with poor prognosis of gastric adenocarcinoma.

PurposeTo investigate the correlation between Nodal and YAP1 expression and the clinicopathological characteristics of gastric adenocarcinoma (GAC).MethodsQuantitative real-time RT-PCR, Western blot, and immunohistochemistry were performed to measure Nodal and YAP1 mRNA and protein in 20 fresh frozen samples and 220 paraffin-embedded GAC tissues with their paired non-tumor mucosa (PNTM). The prognostic values of Nodal and YAP1 were evaluated in 161 GAC patients using univariate and multivariate analyses.ResultsBoth mRNA and protein expression of Nodal and YAP1 were significantly increased in GAC compared to PNTM (P < 0.05). Immunohistochemistry showed that Nodal was more highly expressed in 56.4 % GAC samples compared to PNTM; additionally, Nodal expression correlated with depth of tumor invasion, lymph node metastasis, and distant metastasis (all P < 0.05). There was no association between Nodal and YAP1 in GAC (P = 0.171). Kaplan–Meier analysis showed that the outcome of Nodal-high patients was significantly worse than those with low Nodal expression (χ2 = 30.452, P < 0.001). Cox multivariate regression showed that high Nodal expression was an independent risk factor affecting the prognosis of GAC patients (P = 0.000, RR = 2.976). Furthermore, patients with tumors in which both Nodal and YAP1 were expressed at high levels had the worst prognosis.ConclusionsElevated Nodal expression is a marker of poor prognosis in gastric cancer. Patient outcome is further worsened if Nodal and YAP1 are both expressed in the same tumor. The datas we present here suggest that the inhibition of Nodal signaling may represent a new therapeutic strategy for the treatment of gastric adenocarcinoma.

Retraction] Interleukin-11 induces the expression of matrix metalloproteinase 13 in gastric cancer SCH cells partly via the PI3K-AKT and JAK-STAT3 pathways.

Interleukin (IL)-11 is expressed in the majority of gastric carcinomas and has been associated with an aggressive phenotype and poor prognosis of gastric adenocarcinoma. Matrix metalloproteinase (MMP)-13 has been detected in numerous invasive malignant tumor types and exhibits a broad spectrum of activities on connective tissue components. In this study, we investigated whether IL-11 affects the expression of MMP-13 in human gastric cancer cells, as well as the underlying mechanism. Using western blot assays, we investigated the effect of recombinant human (rh) IL-11 on the expression of MMP-13 in gastric carcinoma cell lines. Using the PI3K inhibitor wortmannin and RNA interference to target the STAT3 gene, we investigated the effects of PI3K inhibition and/or STAT3 depletion on the expression of the MMP-13 protein. Results showed that IL-11 induced MMP-13 expression in a time- and concentration-dependent manner in SCH cells. IL-11 activated PI3K-AKT and JAK-STAT3 signal transduction. Wortmannin and depletion of STAT3 by means of small interfering RNA (siRNA) synergistically reduced the expression of MMP-13. These findings suggested that IL-11 induces the expression of MMP-13 in gastric cancer SCH cells partly via the PI3K-AKT and JAK-STAT3 pathways.

Expression of Fibroblast Growth Factor 10 Is Correlated with Poor Prognosis in Gastric Adenocarcinoma.

Fibroblast growth factor receptor 2 (FGFR2) has been proved to be a significant prognostic factor and a potential therapeutic target in several types of cancer, including gastric cancer. FGFR2 consists two isoforms: FGFR2-IIIb and FGFR2-IIIc, which can be stimulated by different ligands and trigger different downstream signaling pathways. As a specific ligand to FGFR2-IIIb, fibroblast growth factor 10 (FGF10) is expressed in the gastric mesenchyme cell and is involved in stomach development and morphogenesis, but its expression and clinical significance is not well elucidated in gastric cancer. We analyzed FGF10 expression by immunohistochemistry in 178 samples of gastric adenocarcinoma (134 male and 44 female patients, with the average age of 63.2 years old and the average follow-up of 21.6 months). Using the arbitrarily scoring method based on positive cell percentage and staining intensity, we sub-divided the patients into FGF10 high-expression group (58 patients) and low-expression group (120 patients). We thus found that FGF10 expression is significantly associated with lymph node invasion (P = 0.004) and distant metastasis (P = 0.032). Importantly, FGF10 expression is an independent unfavorable prognostic factor (P = 0.042). Moreover, FGF10 knockdown significantly decreased the migration of cultured gastric adenocarcinoma cells, suggesting that FGF10 could promote the invasion of gastric adenocarcinoma. In conclusion, FGF10 expression was identified as a poor prognostic biomarker in gastric adenocarcinoma, and FGF10 could promote the invasion of gastric cancer cells. We suggest that FGF10 could be a potential and promising drug target in gastric adenocarcinoma.

Reduced expression of PTPRD correlates with poor prognosis in gastric adenocarcinoma.

Background PTPRD, encoding protein tyrosine phosphatases receptor type D, is located at chromosome 9p23–24.1, a loci frequently lost in many types of tumors. Recently, PTPRD has been proposed to function as a tumor suppressor gene. The current study aimed to investigate PTPRD expression and its prognostic significance in primary gastric adenocarcinoma.Methods and ResultsQuantitative real time reverse transcription PCR (qRT-PCR) and western blotting were used to examine PTPRD expression in paired gastric tumourous and paracancerous tissues. Compared with the matched normal gastric mucosa tissues, both the mRNA (P = 0.0138) and protein (P = 0.0093) expression of PTPRD in fresh surgical specimens were significantly reduced. Clinicopathological and prognostic roles of PTPRD in gastric adenocarcinoma were investigated using immunohistochemistry with 513 paraffin-embedded gastric adenocarcinoma tissue blocks. Statistical analysis revealed that reduced PTPRD expression was significantly associated with T stage (P = 0.004), TNM stage (P<0.001) and tumor size (P = 0.003). Furthermore, Kaplan-Meier survival analysis revealed that low expression of PTPRD significantly correlated with poor survival of gastric cancer patients (P<0.001). Cox regression analysis confirmed PTPRD expression as independent predictor of the overall survival of gastric cancer patients. The MTT assay determined the effects of PTPRD on cell proliferation of MGC803 and GES1 cell lines. Restoring PTPRD expression in MGC803 cells significantly inhibited their growth rate. Silencing PTPRD expression by siRNA treatment in GES1 significantly enhanced cell proliferation compared with mock siRNA treatment. Methylation analysis of PTPRD promoter CpG island in 3 primary GC samples showed one case with partial methylation.ConclusionsThese results indicated that PTPRD is a candidate tumour suppressor in gastric cancer. Thus, PTPRD may play an important role in gastric tumorigenesis and serve as a valuable prognostic marker of gastric adenocarcinoma.