Potential Prognostic Biomarker For Gastric Cancer Research Articles

BMP6 inhibits gastric cancer growth and predicts good prognosis.

Gastric cancer (GC) is a common tumors in the digestive tract, and effective treatment methods are still lacking. Bone morphogenetic protein 6 (BMP6) is closely related to the occurrence and development of various tumors, but its relevance to GC is still unclear. The aim of the study was to explore the relationship between BMP6 and the occurrence and development of GC. In this study, we investigated the relationship between BMP6 and the prognosis of GC patients using bioinformatics technology and clinical tissue samples. We also explored the connection between BMP6 and the biological behavior of GC cells through molecular biology experiments and relevant in vivo animal experiments. Finally, we examined the mechanisms by which BMP6 inhibits the onset and progression of GC. Through analysis of The Cancer Genomics Atlas (TCGA) database, we observed that BMP6 is expressed at low levels in GC, and its low expression is associated with a poor prognosis in GC patients. Cell experiments demonstrated that BMP6 expression can influence the proliferation of GC cells both in vitro and in vivo. Furthermore, we discovered that BMP6 is linked to the nuclear factor-κB (NF-κB) pathway, and subsequent experiments confirmed that BMP6 can inhibit the biological activity of GC cells by activating the NF-κB pathway. Our findings suggest that BMP6 is a potential prognostic biomarker in GC and can regulate the biological activity of GC cells through the NF-κB pathway. BMP6 may serve as a promising therapeutic target for GC, and our study introduces novel ideas for the prevention and treatment of this disease.

PRKAA1 predicts prognosis and is associated with immune characteristics in gastric cancer.

PRKAA1 is the α-subunit of 5-AMP-activated protein kinase. This study aimed to investigate the role of PRKAA1 expression with multiple clinical parameters, the overall survival rate, blood indexes, and immune infiltration in gastric cancer (GC) patients. We investigated PRKAA1 expression data in GC patients using ELISA, protein atlas, UALCAN, and GEPIA. PRKAA1 expression was associated with immune cell infiltration, and immune cell types were analyzed with the TIMER, DICE, and protein atlas databases. We compared the level of PRKAA1 expression based on the clinical features of GC patients (n = 345). GC patients were divided into two groups based on PRKAA1 expression, and the lymphocyte subsets, overall survival rate, and clinical parameters were compared with peripheral blood mononuclear cell and biochemical indexes. PRKAA1 was highly expressed in the serum of GC patients compared with that of healthy individuals. GC patients with distant metastases, a later TNM stage, and stage IV in UICC exhibited higher PRKAA1 expression. PRKAA1 expression was significantly correlated with circulating T cells. The protein atlas and DICE database results confirmed that PRKAA1 was closely associated with T cells in a single-cell cluster. Furthermore, GC patients with low PRKAA1 expression had better OS rates. PRKAA1 may serve as a potential prognostic biomarker for GC and have an association with immune infiltrates.

INHBB is a novel prognostic biomarker and correlated with immune infiltrates in gastric cancer.

Inhibin subunit beta B (INHBB) is a potential prognostic biomarker for a variety of cancers. However, its role in gastric cancer (GC) remains elusive. The differential expression data of INHBB in tumor and normal tissues were extracted from several databases and genetic alterations of INHBB were assessed by cBioPortal. Kaplan-Meier analysis was used to evaluate the survival rate of patients with GC with INHBB and association with clinical features in GC. Cox regression analysis was used to explore the prognostic value of clinical indicators and INHBB in GC, and a nomogram prognostic model was established. In addition, the predictive validity of the nomogram model was assessed by time-depended receiver operating characteristic (ROC) and calibration curves. Functional enrichment analyses were conducted to functionally annotate INHBB. Notably, we found that the quantitative assessment of immune cell subpopulation infiltration correlated with INHBB expression. INHBB expression is upregulated in GC and is correlated with several clinical features including prognostic indicators and a histological type. Genetic alterations were observed in INHBB, its DNA methylation level was negatively correlated with INHBB expression. High INHBB expression is associated with a poor prognosis and is an independent risk factor for prognosis in GC, along with age and residual tumor. The nomogram model showed a good prediction ability and was validated by time-depended ROC and calibration curves. Functional enrichment analysis indicated that INHBB-associated genes were enriched in tumor microenvironment Gene Ontology (GO) terms and were correlated with tumor-associated pathways. INHBB has a regulatory function in immune cell infiltration, especially macrophage infiltration in GC. Specifically, patients with GC with high INHBB expression and high macrophage infiltration have a worse prognosis. INHBB expression was negatively correlated with the expression of chemokines/chemokine receptors and plays a regulatory role in immunoinhibitor/immunostimulator-involved pathways. INHBB is a potential prognostic biomarker for GC and may drive the abnormal activity of critical cancer-associated pathways, potentially contributing to immune cell infiltration to promote GC development.

Tripartite motif-containing 54 promotes gastric cancer progression by upregulating K63-linked ubiquitination of filamin C.

Tripartite motif (TRIM) proteins have been proved to contribute to cancer progression, while whether tripartite motif-containing 54 (TRIM54) could functionally influence gastric cancer (GC) progression remains elusive. The expression level of TRIM54 and filamin C (FLNC) in GC was determined by Western blot and online database. Cell Counting Kit-8 (CCK-8) assay, colony formation assay and Ethylenediurea (EdU) staining were performed to explore the effects of TRIM54 on GC cell proliferation. Transwell assay and wound healing assay were applied to detect the influence of TRIM54 on GC cell migration and invasion. Bioinformatics analysis and Co-immunoprecipitation assay (Co-Ip), Ubiquitination assay and Half-life assay were involved to explore the regulatory mechanism of TRIM54 on FLNC. TRIM54 was upregulated in GC tissues and cells, and a higher expression level of TRIM54 indicated a shorter overall survival of GC patients. The overexpression of TRIM54 significantly enhanced proliferation, migration, and invasion of GC cells, and inhibition of TRIM54 expression exerted reverse effects on GC cells. Mechanistically, TRIM54 was determined as a post-translational mediator of FLNC, and TRIM54 was co-immunoprecipitated with FLNC and degraded its protein level via K63-linked ubiquitination of FLNC. Notably, FLNC efficiently inhibited GC progression by TRIM54 overexpression. Collectively, our findings suggested that the TRIM54/FLNC axis could be considered as a potential prognostic biomarker for GC.

Expression and prognostic potential of ribosome 18S RNA m6A methyltransferase METTL5 in gastric cancer

BackgroundRibosomal RNA N6-methyltransferase METTL5 was reported to catalyze m6A in 18S rRNA. We aimed to investigate the expression and prognostic features of METTL5 in gastric cancer (GC).MethodsIn this study, 168 GC patients and their corresponding adjacent tissues were collected. Immunohistochemical staining was used to detect the expression of METTL5 protein. Univariate and multivariate Cox analysis were used to dertermine the prognostic role of METTL5 protein in GC, and a nomogram was constructed to evaluate GC patients’ prognosis based on METTL5 expression. Data from TCGA and GEO database were also used to validate the prognostic value of METTL5 in GC patients on mRNA level. We further performed GSEA enrichment analysis to explore the possible function and related pathways related to METTL5.ResultsMETTL5 protein in gastric cancer tissues (GCTs) was significantly decreased compared with adjacent normal tissues (ANTs) and adjacent intestinal metaplasia tissues (AIMTs) (P < 0.001, respectively). Meanwhile, METTL5 expression was negatively correlated with clinicopathologic stage. According to multivariate Cox proportional hazards model analysis, METTL5 protein expression was a good independent predictor of GC prognosis (p < 0.05). Patients with high METTL5 expression had better prognosis. The nomogram constructed based on METTL5 expression could predict the prognosis of GC patients well. GSEA analysis showed that genes of METTL5 low expression group were enriched in some oncogenic signaling pathways such as ERBB, MAPK, JAK-STAT, Wnt, and mTOR, as well as some immune pathways, including Fc-gamma R mediated phagocytosis, Fc-epsilon Ri, chemokine, T cell receptor and B cell receptor signaling pathway. While the high expression group of METTL5 was mainly related to oxidative phosphorylation, nucleotide excision repair and mismatch repair.ConclusionsMETTL5 protein was decreased in GCTs compared with AIMTs and ANTs, and it may be a potential prognostic biomarker in GC.

Moderate Prognostic Value of lncRNA FOXD2-AS1 in Gastric Cancer with Helicobacter pylori Infection.

Gastric cancer (GC) is one of the most frequent tumors worldwide and identification of a sensitive and specific prognostic biomarker is of great importance. Long non-coding RNAs (lncRNAs) play crucial roles in tumorigenesis of various malignancies. In the present study, we investigated lncRNA FOXD2-AS1 expression in gastric tumors and assessed its potential as a prognostic biomarker. A total of 95 tumor and corresponding adjacent non-tumor tissue specimens were collected from patients with GC from Imam Reza hospital, Tabriz, Iran. Total RNA was isolated and FOXD2-AS1 expression was measured using quantitative reverse transcriptase (qRT)-PCR. FOXD2-AS1 was significantly upregulated in tumor samples as compared to non-tumor tissues (P < 0.0001). In addition, higher expression of FOXD2-AS1 was significantly associated with lymph node metastasis and Helicobacter pylori infection. The receiver operating characteristic (ROC) curve analysis revealed that FOXD2-AS1 might be served as a potential prognostic biomarker for GC. FOXD2-AS1 is upregulated in gastric tumors and can be used as a valuable biomarker in the prognosis of patients with GC.

Expression and prognostic significance of thrombospondin gene family in gastric cancer.

Thrombospondins (THBSs) are glycoproteins expressed in the extracellular matrix (ECM) and have critical roles in tumor development and metastasis. However, the diverse expression patterns and prognostic roles of distinct THBS genes in gastric cancer have not been fully elucidated. In the current study, we aimed to investigate the expression patterns of THBSs in gastric cancer (GC) and determine whether they are prognostic markers for this malignancy. mRNA expression status and genetic mutations of THBS family members were performed by using ONCOMINE, UCSC Xena browser, GEPIA, and cBioPortal databases. Prognostic values and function enrichment analysis of the members were assessed via Kaplan-Meier plotter and Metascape. we found that the mRNA expression of THBS1, THBS2, THBS4, and COMP were higher in patients with GC tissues than those in normal gastric mucosa and there was no difference in the mRNA expression of THBS3 between GC and normal tissue. Survival analysis revealed that mRNA levels of THBSs were strongly related to worse OS in GC patients (P<0.05). Overexpression of THBSs indicated poor OS in stage III/IV GC and high expression of THBS1, THBS3, THBS4, and COMP were related to worse OS in stage II GC. Bioinformatics analysis revealed a better understanding the value of THBS family members in GC and suggest that THBSs might serve as potential prognostic biomarkers for GC.

BICC1 as a novel prognostic biomarker in gastric cancer correlating with immune infiltrates

AimBicC family RNA-binding protein 1 (BICC1) codes an RNA-binding protein that regulates gene expression and modulates cell proliferation and apoptosis. We aim at investigating the role of BICC1 in gastric carcinogenesis. MethodsBICC1 mRNA expression in gastric cancer (GC) was examined using the Tumor Immune Estimation Resource (TIMER), The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Correlations between BICC1 expression and clinicopathological parameters were analyzed. The Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan–Meier plotter databases were used to examine the clinical prognostic significance of BICC1 in GC. Signaling pathways related to BICC1 expression were identified by gene set enrichment analysis (GSEA).TIMER and CIBERSORT were used to analyze the correlations among BICC1, BICC1-coexpressed genes and tumor-infiltrating immune cells. ResultsBICC1 was highly expressed in GC and significantly correlated with grade (P = 0.002), TNM stage (P = 0.033), invasion depth (P = 0.001) and vital status (P = 0.009) of GC patients. High BICC1 expression correlated with poor overall survival. The GSEA results showed that cell adhesion-, tumor- and immune- related pathways were significantly enriched in samples with high BICC1 expression. BICC1 and its coexpressed genes were positively related to tumor-infiltrating immune cells and were strongly correlated with tumor-infiltrating macrophages (all r ≥ 0.582, P < 0.0001). The CIBERSORT database revealed that BICC1 correlated with M2 macrophages (P < 0.0001), regulatory T cells (P < 0.0001), resting mast cells (P < 0.0001), activated memory CD4+ T cells (P = 0.002), resting NK cells (P = 0.002), activated dendritic cells (P = 0.002), and follicular helper T cells (P = 0.016). The results from TIMER database confirmed that BICC1 is closely associated with the markers of M2 macrophages and tumor-associated macrophages (all r ≥ 0.5, P < 0.0001). ConclusionBICC1 may be a potential prognostic biomarker in GC and correlates with immune infiltrates.

SP1-activated long noncoding RNA lncRNA GCMA functions as a competing endogenous RNA to promote tumor metastasis by sponging miR-124 and miR-34a in gastric cancer.

Long noncoding RNAs (lncRNAs) were demonstrated to play important roles in gene regulation and cancer progression. However, the functional roles of lncRNAs and the detailed mechanisms underlying gastric cancer (GC) progression remain largely unclear. Here, we identified a novel cancer-related lncRNA, termed lncRNA GCMA (Gastric Cancer metastasis-associated lncRNA), which was upregulated in GC tissues with lymph node metastasis (LNM) compared with tissues without LNM. High expression of GCMA was significantly associated with poor prognosis of patients with GC. Luciferase assays, bioinformatics analyses and chromatin immunoprecipitation (ChIP) assays indicated that SP1 transcription factor directly bound to the GCMA promoter region and activated its transcription. Functionally, upregulation of GCMA dramatically promoted GC cells proliferation, migration and invasion in vitro, whereas knockdown of GCMA elicited the opposite function. Consistently, stable knockdown of GCMA inhibited tumor proliferation, invasion and metastasis in vivo. Mechanistically, by using bioinformatics analyses, RNA binding protein immunoprecipitation (RIP) assays, luciferase assays and western-blot assays, GCMA was demonstrated to function as a competing endogenous RNA (ceRNA) via competitively absorbing miR-124 and miR-34a to upregulate slug and snail, thereby induced epithelial-mesenchymal transition (EMT) and GC cell metastasis in vitro and in vivo. Collectively, these results demonstrate that GCMA functions as an oncogenic lncRNA that may serve as a potential prognostic biomarker for GC and shed new lights on targeted therapy of GC in the future.

Identification of F5 as a Prognostic Biomarker in Patients with Gastric Cancer.

Association of Coagulation factor V (F5) polymorphisms with the occurrence of many types of cancers has been widely reported, but whether it is of prognostic relevance in some cancers remain to be resolved. The RNA-sequencing dataset was downloaded from The Cancer Genome Atlas (TCGA). The potential of F5 genes to predict the survival time of gastric cancer (GC) patients was investigated using univariate and multivariate survival analysis whereas “Kaplan-Meier plotter” (KM-plotter) online tools were employed to validate the outcomes. TCGA data revealed that F5 mRNA levels were significantly upregulated in gastric cancer samples. Survival analysis confirmed that high levels of F5 mRNA correlated with short overall survival (OS) in gastric cancer patients, and the area under the curve (AUC) values of 1-, 2-, and 5-year OS rate were 0.554, 0.593, and 0.603, respectively. Survival analysis by KM-plotter indicated that the high expression of F5 mRNA was significantly associated with a shorter OS compared with the low expression level in all patients with GC, and this was also the case for patients in stage III (hazard ratio (HR) = 1.78, P = 0.017). These findings suggest that the F5 gene is significantly upregulated in GC tumour tissues, and may be a potential prognostic biomarker for GC.

TIGIT and PD-1 may serve as potential prognostic biomarkers for gastric cancer.

Gastric Cancer (GC) is the fifth leading cause of cancer-related death in the world, and in urgent need of specific therapeutic targets to acquire prominent effectiveness. T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are identified to be abnormally overexpressed in various types of cancers including GC. This study aimed to investigate whether TIGIT and PD-1 could serve as potential prognostic biomarkers for GC. Firstly, TCGA GC dataset analysis and correlation analysis were utilized to inspect the relationship between expression of TIGIT, PD-1 and CD8 + T cells in GC and adjacent normal tissues. Then, flow cytometry was used to verify the data after collecting the peripheral blood, GC and adjacent normal tissues from 150 GC patients. Lastly, quantitative RT-PCR was performed to detect the expression of CD155, CD113, CD112 and TIGIT in six human GC cell lines and 631 GC patients in KM Plotter Database to conduct prognostic analysis. As results, we found that TIGIT and PD-1 were upregulated in GC tissues with high CD8 + T cells infiltration, while correlation analysis indicated they were in high-positive correlation. In addition, the flow cytometry analysis further showed that the high-expression of TIGIT in tumor microenvironment of GC could suppress the function of infiltrative CD8 + T cells, which leads to the escape of GC cells from immune killing. Furthermore, CD155 and CD112 were found abnormally upregulated in GC tissues and cell lines and the high expression of CD155, CD112 and TIGIT demonstrated poor prognosis results. In conclusion, these results provided potential therapeutic targets and prognostic biomarkers for treatment of GC in clinic.

Overexpressing PLOD family genes predict poor prognosis in gastric cancer

Procollagen-lysine, 2-oxoglutarate 5-dioxygenases (PLODs) are a set of enzymes involved in the hydroxylation of lysine and stabilization of collagen by crosslinks. Previous studies have highlighted that overexpressing PLOD genes were related to the progression, migration and progression of different human cancers. However, the diverse expression patterns and prognostic values of PLOD genes remain to be elucidated in gastric cancer (GC). In this study, we mined the expression and survival data in GC patients through ONCOMINE, UALCAN and Kaplan-Meier Plotter database. STRING portal couple with DAVID was used to establish a functional protein interaction network of PLOD family genes and analyze the GO and KEGG enriched pathways. Differential gene expression correlated with PLOD family genes was identified with LinkedOmics. We found that PLOD1, 2 and 3 were up-regulated in GC patients compared with normal tissues. High expression levels of PLOD1 and PLOD3 were associated with shorter overall survival (OS), first progression (FP) and post progression survival (PPS) while high expression level of PLOD2 was only associated with shorter FP in all GC patients. Specifically, only high PLOD2 expression had significant correlation with shorter OS, FP and PPS in the diffuse type GC patients. Furthermore, combinatorial use of expressions of all PLOD genes was a superior prognostic indicator for GC patients. Pathway analysis confirmed that PLOD family genes mainly participate in regulating the collagen metabolism and extracellular matrix constitution, and the cellular adaptor protein SHC1, which helps to transduce an extracellular signal into an intracellular signal, could be the regulatory module mediating PLOD's effect on GC. Therefore, we propose that individual PLOD genes or PLOD family genes as a whole could be potential prognostic biomarkers for GC.

Stromal fibroblast activation protein alpha promotes gastric cancer progression via epithelial-mesenchymal transition through Wnt/ \u03b2-catenin pathway

BackgroundTo investigate the influence of fibroblast activation protein alpha (FAP) derived from cancer-associated fibroblasts (CAFs), as well as potential mechanism of epithelial mesenchymal transition (EMT), on gastric cancer (GC) progression.MethodsCorrelation between CAFs-derived FAP and clinical results has been studied by using 60 GC cases. To confirm this relationship, SGC7901 cells were co-cultured with pre-established FAP-overexpressed fibroblasts in vitro and the characteristics including proliferation, migration, invasion and apoptosis abilities were detected subsequently. Meanwhile, SGC and GES1 cells cocultured with FAP-overexpressed fibroblasts were treated with cis-platinum for apoptotic analysis. The underlying EMT was detected by analyzing expression level of E-cadherin, ZO-1, N-cadherin, Vimentin, α-SMA, DKK1 and LEF-1 through western blot and immunofluorescence staining assay. Finally, the tumor-promoting ability of FAP was investigated by utlizing a xenograft gastric cancer nude mouse model.ResultsIt show that FAP has a high-risk correlation with the malignant level of clinical outcomes in GC patients. FAP promotes the ability of proliferation, migration, invasion, apoptosis-inhibition of SGC7901 cells and induces apoptosis of GES1 cells in vitro. The mechanism study shows that epithelial markers have been down-regulated and mesenchymal markers and Wnt/β-catenin signal pathway related proteins have been up-regulated. Animal assay suggests that tumor burden has been enhanced by FAP significantly in vivo.ConclusionsStromal FAP could be a potential prognostic biomarker in GC by promoting cancer progression via EMT through Wnt/ β-catenin signal pathway.

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.

Expression and prognostic value of microRNA-26a and microRNA-148a in gastric cancer.

In our previous study, we demonstrated that four microRNAs (miRNAs) (miR-26a, miR-142-3p, miR-148a, and miR-195) that were downregulated in both plasma and tumor tissues were confirmed to be promising non-invasive diagnostic biomarkers for gastric cancer (GC). We used the quantitative reverse transcription polymerase chain reaction to assess the expression levels of the four miRNAs from paraffin-embedded surgical specimens of GC patients. Kaplan-Meier curves and log-rank test were applied to predict the correlation between miRNAs and cumulative overall survival (OS) of patients with GC. Besides, we performed in vitro assays including cell proliferation, migration, invasion and colony formation, and apoptosis. The median of miRNA expression in paraffin-embedded tissues were used as the cutoff value to classify patients into high or low expression groups. Down-regulation of miR-26a and miR-148a was significantly associated with shorter OS of GC patients either in the test set (miR-26a: P = 0.009; miR-148a: P = 0.005) or the validation set (miR-26a: P = 0.011; miR-148a: P = 0.024). When two sets were combined, Cox regression analysis demonstrated that both of miR-26a and miR-148a were independent prognostic factors for predicting OS of patients with GC (miR-26a: HR = 0.76, 95% CI = 0.61-0.94; miR-148a: HR = 0.73, 95% CI = 0.58-0.91). Furthermore, elevated expression of miR-26 significantly suppressed cell proliferation, migration, invasion and colony formation, and induced apoptosis of MGC-803 cells compared with negative control groups (P < 0.05). These findings supported miR-26a and miR-148a could serve as potential prognostic biomarkers for GC.

Prognostic value of mixed lineage kinase domain-like protein expression in the survival of patients with gastric caner.

The aim of this study was to detect mixed lineage kinase domain-like protein (MLKL) expression in gastric cancer (GC) and to analyze its association with the prognosis of GC patients. Immunohistochemical staining, Western blotting, and quantitative reverse-transcriptase polymerase chain reaction were performed to detect MLKL tissue expression in 117 GC patients. Clinicopathological characteristics and survival data were retrospectively analyzed to discover the clinical importance of MLKL expression. The chi-square test was used to analyze the relationship between MLKL expression and the clinicopathological characteristics. Survival curves were plotted by using the Kaplan-Meier method and compared using the log-rank test. Survival data were evaluated using univariate and multivariate Cox regression analyses. The expression of MLKL mRNA was significantly higher in adjacent normal samples than in the tumor tissues (P = 0.003). Clinicopathological analysis showed that MLKL expression was significantly correlated with age (P = 0.013), histologic type (P = 0.049), differentiation grade (P < 0.001), depth of invasion (P = 0.022), and lymph node metastasis (P = 0.003). Low MLKL expression was significantly associated with decreased overall survival (median 29 months vs. 56 months, P < 0.001). Multivariate analysis suggested that MLKL expression might be an independent prognostic indicator (HR = 0.645, 95% CI, 0.446-1.165, P = 0.002) for GC patients. In conclusion, our findings provide evidence that MLKL might serve as a candidate tumor suppressor and a potential prognostic biomarker for GC.

Low level of FOXL1 indicates a worse prognosis for gastric cancer patients.

The aim of this study was to detect forkhead box L1 (FOXL1) expression in gastric cancer (GC) and to analyze its association with the prognosis of GC patients. Immunohistochemical staining, Western blotting, and quantitative reverse transcriptase polymerase chain reaction were performed to detect FOXL1 tissue expression in 109 GC patients. Clinicopathological characteristics and survival data were retrospectively analyzed to discover the clinical importance of FOXL1 expression. The chi-square test was used to analyze the relationship between FOXL1 expression and the clinicopathological characteristics. Survival curves were plotted by using the Kaplan-Meier method and compared using the log-rank test. Survival data were evaluated using univariate and multivariate Cox regression analyses. The expression of FOXL1 messenger RNA (mRNA) was significantly higher in adjacent normal samples than in the tumor tissues (P = 0.043). Clinicopathological analysis showed that FOXL1 expression was significantly correlated with depth of invasion (P = 0.017), lymph node metastasis (P = 0.019), and distant metastasis (P = 0.047). FOXL1-negative as opposed to the FOXL1-positive patients had lower 5-year overall survival (14.06 vs. 37.78%, P < 0.001). Multivariate analysis suggested that FOXL1 expression might be an independent prognostic indicator (hazard ratio = 0.307, 95% confidence interval, 0.187-0.505; P < 0.001) for GC patients. In conclusion, our findings provide evidence that FOXL1 might serve as a candidate tumor suppressor and a potential prognostic biomarker for GC.

S100A6 as a Potential Serum Prognostic Biomarker and Therapeutic Target in Gastric Cancer

Increased expression of S100A6 in many cancer tissues and its association with tumor behavior and patient prognosis were demonstrated, and there are no studies analyzing the serum levels of S100A6 in patients with gastric cancer (GC). Serum S100A6 levels were investigated as a marker of tumor aggressiveness in patients with GC, and the S100A6 gene was examined as a potential therapeutic target in GC. Serum S100A6 levels were detected in 103 GC patients and 72 healthy subjects by ELISA. Clinicopathological features of GC patients were analyzed in correlation to serum S100A6 levels. Two small interfering RNAs against S100A6 (siRNA1-S100A6 and siRNA2-S100A6) were generated and transfected into SGC7901 cells using pSUPER gfp-neo vector, and the effects of S100A6 knockdown on cell proliferation, invasion and apoptosis were evaluated in vitro. The effects of S100A6 silencing on tumor growth and metastasis were evaluated in vivo in a pseudo-metastatic GC nude mouse model. Serum S100A6 levels were significantly higher in GC patients than in healthy controls (P < 0.001). Serum S100A6 levels were significantly correlated with lymph node metastasis, TNM stage, perineural invasion and vascular invasion. Serum S100A6 level was an independent predictor of overall survival. SiRNA-mediated silencing of S100A6 significantly induced apoptosis and decreased proliferation, clone formation and the invasiveness of GC SGC7901 cells in vitro and significantly reduced tumor volume and number in vivo (P < 0.01). Serum S100A6 level may serve as a potential prognostic biomarker in GC. Inhibition of S100A6 decreased the metastatic potential of GC cells.