Poor Prognosis In Gastric Cancer Research Articles

High soluble OX40 levels correlate with metastatic gastric cancer.

Previous studies demonstrated an association between OX40+T cell expression with poor prognosis in gastric cancer (GC). The soluble form of OX40 (sOX40) could block the interactions between OX40 on the effector T cell, and it is a ligand (OX40L) in dendritic cells. However, the role of sOX40 as a pretreating biomarker and prognostic predictor remains unclear. This study aimed to evaluate the association of levels of sOX40 and sOX40L with disease progression in GC. Between 2017 and 2018, a cross-sectional study was performed on 83 GC patients and 20 healthy controls. Among 83 GC patients (median of 63 years), 32.4% of patients with I/II stages, 42.3% III, and 25.3% in IV stages. Metastatic GC patients had significantly higher levels of soluble OX40 compared with stage III (p = 0.0003) and early stages I and II patients (p = 0.005). There was no significant differences in the sOX40 and sOX40L levels between Lauren's histological subtype (intestinal, diffuse, and mixed). This study showed that soluble OX40 levels have an essential role in GC progression. OX40 molecules may constitute a predictor for poor prognosis and a potential target for immunotherapy in GC.

Prognostic role of myeloid-derived tumor-associated macrophages at the tumor invasive margin in gastric cancer with liver metastasis (GCLM): a single-center retrospective study.

Liver metastasis is one of the important factors leading to poor prognosis of gastric cancer. According to the classic "seed soil theory", it is speculated that the liver microenvironment at the invasion margin of gastric cancer liver metastases (GCLM) may have a crucial impact on tumor progression. However, few studies had stated the correlation between the patients' prognosis and the densities of stromal cells infiltrating into the invasive margin, where our retrospective study designed to identify the role of infiltrating macrophages on the prognosis of GCLM as a reliable supplement of predictive tumor markers. The material consisted of a group of 72 gastric cancer (GC) patients with liver metastasis diagnosed from February 2015 and December 2020. The CD68+, CD206+, and Clec4f+ macrophages in their specimens were counted by immunohistochemistry (IHC), and the analysis area was the invasive margin of metastatic lesions. Clinical data were collected retrospectively. Overall survival (OS) was calculated from the date of initial diagnosis to the date of last follow-up or death. Survival analyses were performed using the Kaplan-Meier method and log-rank test. Multivariate Cox regression was performed to asses impact of macrophages on OS. The expression of CD206 could indicate the prognosis of patients with GCLM, and patients with high expression of CD206 had worse prognoses (P=0.0002). Univariate and multivariate analyses showed that CD206 was an independent risk factor for prognosis (HR 5.276, 95% CI: 1.730-16.089, P=0.003). The CD206+ myeloid-derived tumor associated macrophages (TAMs) may predict whether patients could benefit from R1 resection of liver-metastatic lesions, which has important theoretical significance and practical value for accurately evaluating the clinical prognosis of patients with GCLM and guiding clinical treatment.

Tumor-derived IL-8 facilitates lymph node metastasis of gastric cancer via PD-1 up-regulation in CD8+ T cells

BackgroundThe pretherapeutic serum interleukin-8 (sIL-8) levels have been revealed to be increased in about half of patients with locally advanced gastric cancer. However, the roles of IL-8 in lymph node metastasis (LNM) and the underlying mechanisms remain unclear.Methods146 patients with primary gastric carcinoma were enrolled in this study. ELISA was used to measure IL-8 levels. The CD4/CD8 ratio and programmed cell death-1 (PD-1) expression of T cells in primary tumor tissues, tumor-draining lymph nodes (TDLNs) and non-draining lymph nodes (NDLNs) were assayed with flow cytometry. Protein expression of the molecules was determined with immunohistochemistry, western blotting or immunoprecipitation. The gastric cancer mouse tumor model with LNM was utilized to determine the role of IL-8 in regulation of tumor metastasis and progression.ResultsThe elevated sIL-8 levels were associated with LNM and poor prognosis in gastric cancer. Furthermore, sIL-8 was identified to be prominently produced by gastric cancer-associated fibroblasts (CAFs). Elevated IL-8 can up-regulate PD-1 expression in CD8+ T cells, resulting in immunosuppression in primary tumors and TDLNs, which enhances LNM of gastric cancer. Molecularly, IL-8 increases PD-1 expression through JAK2/STAT3 signaling activation, and inhibits its ubiquitination via Fbxo38 down-regulation. In addition, the in vivo studies in mouse gastric cancer model demonstrated that IL-8 promotes LNM via PD-1 up-regulation in CD8+ T cells.ConclusionThe present study elucidates the pro-metastatic role of elevated IL-8 in gastric cancer, and provides novel insights to enhance immune checkpoint blockade therapy for anti-PD-1 in gastric cancer.

Aberrant ARMCX1 Expression Is an Independent Predictor of Poor Prognosis in Gastric Cancer.

ARMCX1 (Armadillo repeat containing X-linked 1) is identified to be the novel tumor suppressor gene related to multiple tumor types. Nonetheless, its effect on gastric cancer (GC) is still poorly understood. The present work determined ARMCX1 level within GC and the relation with clinicopathological characteristics. This work also collected relevant information in The Cancer Genome Atlas (TCGA) database for investigating associations of ARMCX1 with clinicopathologic variables and then validated in our GC cohort. Receiver operating characteristic (ROC) curves were plotted for assessing whether ARMCX1 expression was significant in diagnosing GC. Kaplan-Meier (KM) and Cox regression analyses were conducted for assessing clinicopathological characteristics associated with overall survival (OS) of GC cases. The data from the Human Protein Atlas (HPA) and Gene Expression Omnibus (GEO) databases was also analyzed for further validation, and biological processes (BPs) were identified by gene set enrichment analysis (GSEA). GC tissues showed markedly decreased ARMCX1 level relative to healthy counterparts (P < 0.001). Interestingly, ARMCX1 upregulation predicted low differentiation, poor OS, increased invasion, and late tumor stage. In addition, the area under ROC curve (AUC) and P value were 0.747 and <0.001, separately. Cases showing ARMCX1 upregulation showed significantly poor prognostic outcome compared with patients showing downregulation (P = 0.007). Furthermore, multivariate analysis showed that ARMCX1 upregulation independently predicted the risk of OS (P = 0.0017, hazard ratio, 1.089). GSEA analysis identified that several cancer-related pathways, such as focal adhesion, ECM receptor interaction, JAK/STAT, melanoma, WNT, and cancer, were enriched in GCs. We conclude that ARMCX1 serves as the possibly independent biomarker to diagnose and predict GC prognostic outcome.

Modulation of p53 expression in cancer-associated fibroblasts prevents peritoneal metastasis of gastric cancer

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are associated with the establishment and progression of peritoneal metastasis. This study investigated the efficacy of replicative oncolytic adenovirus-mediated p53 gene therapy (OBP-702) against CAFs and peritoneal metastasis of gastric cancer (GC). Higher CAF expression in the primary tumor was associated with poor prognosis of GC, and higher CAF expression was also observed with peritoneal metastasis in immunohistochemical analysis of clinical samples. And, we found transcriptional alteration of p53 in CAFs relative to normal gastric fibroblasts (NGFs). CAFs increased the secretion of cancer-promoting cytokines, including interleukin-6, and gained resistance to chemotherapy relative to NGFs. OBP-702 showed cytotoxicity to both GC cells and CAFs but not to NGFs. Overexpression of wild-type p53 by OBP-702 infection caused apoptosis and autophagy of CAFs and decreased the secretion of cancer-promoting cytokines by CAFs. Combination therapy using intraperitoneal administration of OBP-702 and paclitaxel synergistically inhibited the tumor growth of peritoneal metastases and decreased CAFs in peritoneal metastases. OBP-702, a replicative oncolytic adenovirus-mediated p53 gene therapy, offers a promising biological therapeutic strategy for peritoneal metastasis, modulating CAFs in addition to achieving tumor lysis.

Expression of Matrix Metalloproteinase-7 Predicts Poor Prognosis in Gastric Cancer.

To date, no potential markers have been established for predicting prognosis in gastric cancer. Matrix metalloproteinase-7 (MMP-7) has been suggested as a prognostic marker in several cancers. In this study, we aimed to determine the expression of the MMP-7 protein and its polymorphisms in gastric cancer tissues. The association between MMP-7 expression level and clinicopathological characteristics was also evaluated. MMP-7 protein expression and its polymorphisms were investigated in a total of 400 patients using immunohistochemistry and TaqMan SNP genotyping assays. The correlation of MMP-7 expression with clinicopathological characteristics, including tumor location, tumor size, histologic type, lymphatic invasion, vascular invasion, pathological T stage, pathological TNM stage, residual tumor, and CEA level, was investigated. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a multivariate Cox proportional hazards regression model. MMP-7 expression was found in 283 of 400 (70.75%) gastric cancer tissues. Expression of MMP-7 was significantly associated with poor clinicopathological characteristics, including vascular invasion (OR = 6.61, 95%CI = 4.26–9.89, p = 0.024), lymphatic invasion (OR = 8.17, 95%CI = 4.47–12.39, p = 0.017), undifferentiated histologic type (OR = 2.46; 95% CI, 1.31–4.52; p = 0.014), higher TNM stage (stage IV) (OR = 1.48, 95%CI = 1.08–3.08, p = 0.047), and high CEA level (OR = 5.96, 95%CI = 2.12–8.12, p = 0.026). We further observed a significant association of the variant genotype; gastric cancer patients carrying GG of MMP-7 (-181A/G; rs11568818) had a greater increased risk of MMP-7 expression than did wild-type (WT) carriers (AG: odds ratio (OR) = 5.67; 95%CI = 1.57–7.23; p = 0.024 and GG: OR = 8.32; 95%CI = 2.94–11.42; p = 0.016). These findings suggest that MMP-7 expression can be used to predict the prognosis of gastric cancer patients.

JAK-STAT1 Signaling Pathway Is an Early Response to Helicobacter pylori Infection and Contributes to Immune Escape and Gastric Carcinogenesis.

Helicobacter pylori infection induces a number of pro-inflammatory signaling pathways contributing to gastric inflammation and carcinogenesis and has been identified as a major risk factor for the development of gastric cancer (GC). Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates immune regulatory processes, including tumor-driven immune escape. Programmed death ligand 1 (PD-L1) expressed on gastric epithelium can suppress the immune system by shutting down T cell effector function. In a human cohort of subjects with gastric lesions and GC analyzed by proteomics, STAT1 increased along the cascade of progression of precancerous gastric lesions to GC and was further associated with a poor prognosis of GC (Hazard Ratio (95% confidence interval): 2.34 (1.04–5.30)). We observed that STAT1 was activated in human H. pylori-positive gastritis, while in GC, STAT1, and its target gene, PD-L1, were significantly elevated. To confirm the dependency of H. pylori, we infected gastric epithelial cells in vitro and observed strong activation of STAT1 and upregulation of PD-L1, which depended on cytokines produced by immune cells. To investigate the correlation of immune infiltration with STAT1 activation and PD-L1 expression, we employed a mouse model of H. pylori-induced gastric lesions in an Rnf43-deficient background. Here, phosphorylated STAT1 and PD-L1 were correlated with immune infiltration and proliferation. STAT1 and PD-L1 were upregulated in gastric tumor tissues compared with normal tissues and were associated with immune infiltration and poor prognosis based on the TCGA-STAD database. H. pylori-induced activation of STAT1 and PD-L1 expression may prevent immune surveillance in the gastric mucosa, allowing premalignant lesions to progress to gastric cancer.

Identification of the upstream regulators of KDM5B in gastric cancer

AimsLysine-specific demethylase 5B (KDM5B) is an epigenetic regulator of chromatin that catalyzes the demethylation of histone 3 lysine 4. It is overexpressed in multiple cancer types and acts as a therapeutic target in cancer therapy. Nevertheless, its upstream regulatory pathway is not completely understood, prompting the search for the underlying biological factors driving KDM5B overexpression. Materials and methodsA comprehensive analysis was performed to examine the association between KDM5B overexpression and copy number variation (CNV), somatic mutation, mRNA expression, miRNA expression, and clinical characters from The Cancer Genome Atlas database. Coexpression and function enrichment analyses were performed with KDM5B-coexpressed genes. The gastric cancer (GC) cell line MKN45 was utilized to verify the regulation of KDM5B using the transcription factor (TF) Yin Yang 1 (YY1) and miR-29a-3p. Key findingsKDM5B was overexpressed and associated with poor prognosis in GC. KDM5B upregulation was driven by CNV amplification and DNA hypomethylation rather than by KDM5B mutations. Enrichment analysis revealed that KDM5B-coexpressed genes were primarily related to the transmembrane transport function and the ubiquitin-mediated proteolysis signaling pathway. As a TF, YY1 might bind to the KDM5B promoter region to regulate KDM5B expression. In addition, miR-29a-3p might bind to and negatively regulate KDM5B expression. SignificanceOur results demonstrate that KDM5B expression is regulated via CNV amplification, DNA hypomethylation, and YY1 and miR-29a-3p; KDM5B expression regulation is associated with patient survival and tumor cell proliferation.

Novel Biomarkers of microRNAs in Gastric Cancer: An Overview from Diagnosis to Treatment

Abstract: Gastric cancer (GC) is the fourth most frequent disease in the world and the second cause of cancer-related death. In this way, over 80% of diagnoses are made in the middle to advanced de-grees of the disease, underscoring the requirement for innovative biomarkers that can be identified quickly. Meaningly, biomarkers that can complement endoscopic diagnosis and be used to detect patients with a high risk of GC are desperately needed. These biomarkers will allow for the accurate prediction of therapy response and prognosis in GC patients, as well as the development of an opti-mal treatment strategy for each individual. Conspicuously, microRNAs (miRNAs) and small non-coding RNA regulate the expression of target mRNA, thereby modifying critical biological mecha-nisms. According to the data, abnormally miRNAs expression in GC is linked to tumor growth, car-cinogenesis, aggression, and distant metastasis. Importantly, miRNA expression patterns and next-generation sequencing (NGS) can also be applied to analyze different kinds of tissues and cancers. Given the high death rates and poor prognosis of GC, and the absence of a clinical diagnostic factor that is adequately sensitive to GC, research on novel sensitive and specific markers for GC diagno-sis is critical. In this review, we examine the latest research findings that suggest the feasibility and clinical utility of miRNAs in GC.

RBMS1 promotes gastric cancer metastasis through autocrine IL-6/JAK2/STAT3 signaling

Metastasis is the most important reason for the poor prognosis of gastric cancer (GC) patients, and the mechanism urgently needs to be clarified. Here, we explored a prognostic model for the estimation of tumor-associated mortality in GC patients and revealed the RNA-binding protein RBMS1 as a candidate promoter gene for GC metastasis by analyzing GOBO and Oncomine high-throughput sequencing datasets for 408 GC patients. Additionally, RBMS1 was observed with overexpression in 85 GC patient clinical specimens by IHC staining and further be verified its role in GC metastasis via inducing EMT process both in in vitro and in vivo experiments. Moreover, we identified that IL-6 was predicted to be one of the most significant upstream cytokines in the RBMS1 overexpression gene set based on the Ingenuity Pathway Analysis (IPA) algorithm. Most importantly, we also revealed that RBMS1 could promote migration and invasion through IL6 transactivation and JAK2/STAT3 downstream signaling pathway activation by influencing histone modification in the promoter regions after binding with the transcription factor MYC in the HGC-27 and SGC-7901 GC cell lines. Hence, we shed light on the potential molecular mechanisms of RBMS1 in the promotion of GC metastasis, which suggests that RBMS1 may be a potential therapeutic target for GC patients.

Low Expression of ZNF154 is Related to Poor Prognosis in Gastric Cancer

IntroductionZinc finger protein 154 (ZNF154) has been identified as a tumor suppressor gene in multiple carcinomas. Lymph node (LN) metastasis is one of the most intensively negative factor of gastric cancer (GC) prognosis. However, the potential mechanisms of ZNF154-mediated LN metastasis are not elucidated. This study aimed to investigate the role of ZNF154 in LN metastasis of GC and their underlying mechanisms through in vitro and in vivo experiments.MethodsAntitumor effect was measured by growth inhibition by cell counting kit-8 (CCK-8) and colony formation assay. Cell cycle distribution and apoptosis were evaluated by flow cytometry. Cell migration and invasion were measured by wound healing and transwell invasion assays, respectively. The expression levels of proteins were analyzed by Western blot. Xenograft models were used for validation in vivo.ResultsOur research showed that ZNF154 was down-regulated in 81.43% (57 of 70) of GC tissues compared with 58.6% of paired non-tumor tissues from patients, ZNF154 was down-regulated in 100% (7 of 7) of GC cell lines, up-regulated expression of ZNF154 in MGC-803 GC cells reduced cell proliferation, viability, migration and invasion, and enhanced cell apoptosis and arrested cell cycle in G2 phase, and suppressed tumorigenicity of MGC-803 cells in mice. Furthermore, up-regulated expression of ZNF154 mRNA reduced the expression of B-cell lymphoma-2 (Bcl-2), matrix metalloproteinase 2 (MMP-1), hepatocyte growth factor (HGF), vascular endothelial growth factor-A/C (VEGF-A/C).ConclusionZNF154 inhibited LN metastasis of GC cells by suppressing several biological events of GC cells. ZNF154 was a tumor suppressor gene that is a promising target for blocking nodal involvement in GC.

Alpha-fetoprotein can promote gastric cancer progression via upregulation of metastasis-associated colon cancer 1.

High serum alpha-fetoprotein (AFP) level is a predictor of poor prognosis in patients with gastric cancer (GC). AFP-producing GC (AFP-GC) is an aggressive subtype of GC characterized by a high incidence of liver metastasis and high c-Met expression. High expression of metastasis-associated colon cancer 1 (MACC1), which is the transcription activator of c-Met, also predicts a poor prognosis of GC. c-Met is known to be involved in tumor progression into malignant invasive phenotypes. Considering that high c-Met expression is simultaneously positively correlated with high AFP and MACC1 expression levels and that high expression of AFP or MACC1 predicts poor prognosis in GC, we hypothesized that an interaction may exist between AFP and MACC1. In the present study, GC cell lines with AFP-overexpression, MACC1-downregulation and the combination of both transfections were used as experimental models. The relative mRNA and protein expression of c-Met, AFP and MACC1 were analyzed using reverse transcription quantitative PCR and western blotting, respectively. Cell viability was evaluated using Cell Counting Kit-8 assay. Cell invasion and cell migration were examined using Transwell migration assay with and without Matrigel, respectively. The results demonstrated that, compared with the control group, the mRNA and protein expression of MACC1was significantly elevated in the AFP-overexpressed group and in the group with AFP overexpressed and MACC1 downregulated. Furthermore, a significantly enhanced cell viability, migration and invasion were observed in the AFP-overexpressing group, whereas opposite effects were found in the MACC1-downregulating group. In summary, the results from this study indicated that AFP may promote GC progression by stimulating MACC1. This finding may help illustrating the aggressive behaviors of GC in patients with high AFP serum level and AFP-GC.

Long noncoding RNA FAM225A promotes the malignant progression of gastric cancer through the miR-326/PADI2 axis

Gastric cancer (GC) is a global health problem and further studies of its molecular mechanisms are needed to identify effective therapeutic targets. Although some long noncoding RNAs (lncRNAs) have been found to be involved in the progression of GC, the molecular mechanisms of many GC-related lncRNAs remain unclear. In this study, a series of in vivo and in vitro assays were performed to study the relationship between FAM225A and GC, which showed that FAM225A levels were correlated with poor prognosis in GC. Higher FAM225A expression tended to be correlated with a more profound lymphatic metastasis rate, larger tumor size, and more advanced tumor stage. FAM225A also promoted gastric cell proliferation, invasion, and migration. Further mechanistic investigation showed that FAM225A acted as a miR-326 sponge to upregulate its direct target PADI2 in GC. Overall, our findings indicated that FAM225A promoted GC development and progression via a competitive endogenous RNA network of FAM225A/miR-326/PADI2 in GC, providing insight into possible therapeutic targets and prognosis of GC.

Characteristics of the Immune Cell Infiltration Landscape in Gastric Cancer to Assistant Immunotherapy.

Background: Gastric cancer (GC) was usually associated with poor prognosis and invalid therapeutical response to immunotherapy due to biological heterogeneity. It is urgent to screen reliable indices especially immunotherapy-associated parameters that can predict the therapeutic responses to immunotherapy of GC patients. Methods: Gene expression profile of 854 GC patients were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets (GSE84433) with their corresponding clinical and somatic mutation data. Based on immune cell infiltration (ICI) levels, molecular clustering classification was performed to identify subtypes and ICI scores in GC patients. After functional enrichment analysis of subtypes, we further explored the correlation between ICI scores and Tumor Mutation Burden (TMB) and the significance in clinical immunotherapy response. Results: Three subtypes were identified based on ICI scores with distinct immunological and prognostic characteristics. The ICI-cluster C, associated with better outcomes, was characterized by significantly higher stromal and immune scores, T lymphocytes infiltration and up-regulation of PD-L1. ICI scores were identified through using principal component analysis (PCA) and the low ICI scores were consistent with the increased TMB and the immune-activating signaling pathways. Contrarily, the high-ICI score cluster was involved in the immunosuppressive pathways, such as TGF-beta, MAPK and WNT signaling pathways, which might be responsible for poor prognosis of GC. External immunotherapy and chemotherapy cohorts validated the patients with lower ICI scores exhibited significant therapeutic responses and clinical benefits. Conclusion: This study elucidated that ICI score could sever as an effective prognostic and predictive indicator for immunotherapy in GC. These findings indicated that the systematic assessment of tumor ICI landscapes and identification of ICI scores have crucial clinical implications and facilitate tailoring optimal immunotherapeutic strategies.

LncRNA/miR-29c-Mediated High Expression of LOX Can Influence the Immune Status and Chemosensitivity and Can Forecast the Poor Prognosis of Gastric Cancer.

Gastric carcinoma is the fourth most prevalent cause of cancer-related deaths worldwide because of dismal prognosis and few therapeutic options. Accumulated studies have indicated that targeting lysyl oxidase (LOX) family members may serve as an anticancer strategy. Nevertheless, the specific mechanisms of LOX in stomach carcinoma are still unclear. In this study, we demonstrated that LOX is significantly different in 13 types of cancers and may act as a potential therapeutic target, especially in stomach carcinoma. Moreover, overexpression of LOX in gastric carcinoma was validated by multiple databases and contributed to the poor overall survival (OS), progression-free survival (PFS) and post-progression survival (PPS) of stomach adenocarcinoma (STAD) patients. Next, based on the ceRNA hypothesis, the HIF1A-AS2/RP11-366L20.2-miR-29c axis was characterized as the upstream regulatory mechanism of LOX gene overexpression in gastric cancer by combining correlation analysis, expression analysis, and survival analysis. Finally, we illustrated that LOX gene overexpression leads to dismal prognosis of gastric cancer, perhaps through promoting M2 macrophage polarization and tumor immune escape and enhancing drug resistance of tumor cells to chemotherapeutic drugs. Our research demonstrate that LOX may be potentially applied as a novel prognostic marker and targeting inhibition of LOX holds promise as a treatment strategy for gastric cancer.

Dysregulation of let-7c-5p/Tyrosyl-DNA phosphodiesterase 1 axis indicates an unfavorable outcome in gastric cancer

Introduction Tyrosyl-DNA phosphodiesterase 1 (TDP1) can repair oxidative damage-caused 3′-phosphoglycolates and promote cancer progression. However, the clinical significance of TDP1 and its correlation with microRNAs (miRNAs) in gastric cancer (GC) remains unknown. Methods The relationship of TDP1 or let-7c-5p with the clinical outcomes of GC was determined by a tissue microarray and TCGA dataset. Cell viability and invasion were assessed by MTT and Transwell assays. Pearson correlation analysis, luciferase gene report, qRT-PCR, and Western blot analyses were used to analyze the interaction between TDP1 and let-7c-5p in GC tissues and cells. Results We found that TDP1 expression was elevated in GC tissues and associated with the dysregulation of let-7c-5p. Knockdown of TDP1 inhibited GC cell proliferation and invasion. let-7c-5p could be found to bind with TDP1, reduce its expression levels, and represent a predictive marker in GC. Conclusion Our findings demonstrated that dysregulation of let-7c-5p/TDP1 axis could predict a poor prognosis in GC.

ASF1b is a novel prognostic predictor associated with cell cycle signaling pathway in gastric cancer.

Gastric cancer (GC) is one of the most common malignant tumors with poor outcomes. Identification of new therapeutic targets is urgently needed. Accumulating evidence has shown that anti-silencing function 1b (ASF1b) contributes to the progression in multiple cancer types. However, detailed mechanisms of ASF1b tumorigenesis in gastric cancer remain elusive. This study showed that ASF1b was upregulated in GC tissues and remarkably correlated with TNM stage, histological grade and poor prognosis of GC. We induced down and up-regulation of ASF1b in GC cell lines and monitored the changes in their biological behavior. Furthermore, loss of ASF1b was efficient to suppress subcutaneous xenograft tumor growth in vivo. We demonstrate that ASF1b is involved in regulation of cell cycle and PI3K/AKT/mTOR signaling through experiments and database analysis. Mechanistically, ASF1b promoted the proliferation, migration and invasion of GC cells. Taken together, this study highlights the role of ASF1b, which provided new insights into the underlying mechanism of progression and metastasis in GC for the first time.

The EMT-induced lncRNA NR2F1-AS1 positively modulates NR2F1 expression and drives gastric cancer via miR-29a-3p/VAMP7 axis

Deregulated lncRNAs play critical roles in tumorigenesis and tumor progression. NR2F1-AS1 is an antisense lncRNA of NR2F1. However, the biological function of NR2F1-AS1 in gastric cancer (GC) remains largely unclear. In this study, we revealed that NR2F1-AS1 and NR2F1 were both positively correlated with the degree of malignancy and predicted poor prognosis in two independent GC cohorts. Besides, NR2F1-AS1 and NR2F1 can respond to Epithelial-to-mesenchymal transition (EMT) signaling in GC, since their expression was increased by TGF-beta treatment and decreased after stable overexpression of OVOL2 in GC cell lines. NR2F1-AS1 and NR2F1 were highly co-expressed in pan-tissues and pan-cancers. Depletion of NR2F1-AS1 compromised the expression level of NR2F1 in GC cells. Furthermore, NR2F1-AS1 knockdown inhibited the proliferation, migration, invasion and G1/S transition of GC cells. More importantly, transcriptome sequencing revealed a novel ceRNA network composed of NR2F1-AS1, miR-29a-3p, and VAMP7 in GC. The overexpression of VAMP7 predicted poor prognosis in GC. Rescue assay confirmed that NR2F1-AS1 promotes GC progression through miR-29a-3p/VAMP7 axis. Our finding highlights that the aberrant expression of NR2F1-AS1 is probably due to the abnormal EMT signaling in GC. LncRNA NR2F1-AS1 plays crucial roles in GC progression by modulating miR-29a-3p/VAMP7 axis, suggesting that NR2F1-AS1 may serve as a potential therapeutic target in GC.

LINC01094 Predicts Poor Prognosis in Patients With Gastric Cancer and is Correlated With EMT and Macrophage Infiltration.

Objectives: The novel long non-coding RNA (lncRNA) LINC01094 is often upregulated in renal cell carcinoma and glioma; however, its role in gastric cancer remains unclear. Here, we aim to demonstrate the relationship between LINC01094 and gastric cancer. Method: The gene expression (RNASeq) data of 375 patients with localized, locally advanced, and metastatic gastric cancer were extracted from The Cancer Genome Atlas. The Kruskal–Wallis test, Wilcoxon signed-rank test, and logistic regression were used to analyze the relationship between the clinicopathological characteristics and LINC01094 expression. Cox regression analysis and the Kaplan–Meier method were used to assess prognostic factors of gastric cancer. A nomogram based on Cox multivariate analysis was used to predict the impact of LINC01094 on gastric cancer prognosis. Gene set enrichment analysis (GSEA) was used to identify key LINC01094-associated signaling pathways. Fluorescence in situ hybridization (FISH) was performed to detect the location of LINC01094 in the tissue, and a competing endogenous (ce)RNA network was constructed to identify LINC01094-related genes. Spearman's rank correlation was used to elucidate the association between LINC01094 expression level and immune cell infiltration level. Result: LINC01094 expression was upregulated in gastric cancer tissues and strongly associated with overall survival using univariate Cox regression (hazard ratio [HR] = 1.476, 95% CI = 1.060-2.054, P = .021) and multivariate Cox regression analysis (HR = 1.535, 95% CI = 1.021-2.308, P = .039). The area under the receiver operating characteristic curve of LINC01094 was 0.910. GSEA showed a strong relationship between LINC01094 and the epithelial-mesenchymal transition pathway. RNA-FISH demonstrated that LINC01094 localized in the cytoplasm. It was closely related to the epithelial-mesenchymal transition (EMT) marker SNAI2, according to ceRNA (R = 0.61, P < .001), and macrophage-related gene FCGR2A. Macrophages were also significantly positively correlated with LINC01094 expression (R = 0.747, P < .001). Conclusion: High LINC01094 expression predicts poor prognosis in gastric cancer and is correlated with the epithelial-mesenchymal transition pathway and macrophage infiltration.

High Expression of Pregnancy Specific Beta-1-glycoprotein 1 Is Associated With Poor Gastric Cancer Prognosis.

Pregnancy specific beta-1-glycoprotein 1 (PSG1) is a member of the immunoglobulin superfamily and associated with carcinoembryonic antigens. It has been reported to be highly expressed in variety of cancers. However, the role of PSG1 in gastric cancer remains unclear. The aim of our study was to examine the clinical significance and functional role of PSG1 in gastric cancer. We analyzed the association between PSG1 expression levels and clinicopathological features using Kaplan-Meier survival curves and publicly available microarray data. In gastric cancer cell lines, PSG1 expression levels were detected by polymerase chain reaction and western blot analysis. The functional role of PSG1 on the proliferation, migration and invasive abilities were also investigated using PSG1 siRNA or an over-expression plasmid vector through WST, transwell migration and invasion assays. PSG1 expression levels were higher in gastric cancer patient tissues than in normal gastric tissues. Increased expression of PSG1 was associated with poor patient prognosis. Knockdown of PSG1 inhibited cell proliferation, migration, and invasion in gastric cancer cells. In contrast, over-expression of PSG1 enhanced cell proliferation, migration, and invasion. PSG1 is up-regulated in gastric cancer and may serve as an oncogene that promotes cell proliferation, migration, and invasion. PSG1 is an independent prognostic factor for the progression of gastric cancer and may be a potential biomarker and therapeutic target for gastric cancer.