Tissues Of Gastric Cancer Patients Research Articles

Clinical Significance of HRNR Expression in Patients With Stage II/III Gastric Cancer After Curative Gastrectomy.

The function of the S-100 protein family member hornerin (HRNR) in gastric cancer (GC) tissues is largely unknown. We researched the clinical significance of HRNR expression in GC tissues of patients with pathological (p)Stage II/III GC after curative resection. We included patients with pStage II/III GC who underwent curative gastrectomy (n=253). Expression levels of HRNR in GC tissue and in the adjacent normal mucosa were determined using quantitative real-time polymerase chain reaction. Clinicopathological features and overall survival (OS) were compared in patients with different HRNR expression levels in GC tissue. HRNR expression levels were significantly higher in GC tissues than in the adjacent normal mucosa. HRNR expression level in GC tissue showed sex differences. The 5-year OS rate in the high-HRNR expression group was significantly worse than that in the low-expression group (5-year survival 53.6% vs. 74.9%; p=0.004). Furthermore, on multivariate analysis, high-HRNR expression was an independent predictor of poor OS (hazard ratio=1.534; 95% confidence interval=1.130-2.618; p=0.011). In patients with pStage II/III GC after curative gastrectomy, HRNR expression in GC tissue may be a useful prognostic marker.

Acyltransferase zinc finger DHHC-type containing 2 aggravates gastric carcinoma growth by targeting Nrf2 signaling: A mechanism-based multicombination bionic nano-drug therapy

The significant regulatory role of palmitoylation modification in cancer-related targets has been demonstrated previously. However, the biological functions of Nrf2 in stomach cancer and whether the presence of Nrf2 palmitoylation affects gastric cancer (GC) progression and its treatment have not been reported. Several public datasets were used to look into the possible link between the amount of palmitoylated Nrf2 and the progression and its outcome of GC in patients. The palmitoylated Nrf2 levels in tumoral and peritumoral tissues from GC patients were also evaluated. Both loss-of-function and gain-of-function via transgenic experiments were performed to study the effects of palmitoylated Nrf2 on carcinogenesis and the pharmacological function of 2-bromopalmitate (2-BP) on the suppression of GC progression in vitro and in vitro. We discovered that Nrf2 was palmitoylated in the cytoplasmic domain, and this lipid posttranslational modification causes Nrf2 stabilization by inhibiting ubiquitination, delaying Nrf2 destruction via the proteasome and boosting nuclear translocation. Importantly, we also identify palmitoyltransferase zinc finger DHHC-type palmitoyltransferase 2 (DHHC2) as the primary acetyltransferase required for the palmitoylated Nrf2 and indicate that the suppression of Nrf2 palmitoylation via 2-bromopalmitate (2-BP), or the knockdown of DHHC2, promotes anti-cancer immunity in vitro and in mice model-bearing xenografts. Of note, based on the antineoplastic mechanism of 2-BP, a novel anti-tumor drug delivery system ground 2-BP and oxaliplatin (OXA) dual-loading gold nanorods (GNRs) with tumor cell membrane coating biomimetic nanoparticles (CM@GNRs-BO) was established. In situ photothermal therapy is done using near-infrared (NIR) laser irradiation to help release high-temperature-triggered drugs from the CM@GNRs-BO reservoir when needed. This is done to achieve photothermal/chemical synergistic therapy. Our findings show the influence and linkage of palmitoylated Nrf2 with tumoral and peritumoral tissues in GC patients, the underlying mechanism of palmitoylated Nrf2 in GC progression, and novel possible techniques for addressing Nrf2-associated immune evasion in cancer growth. Furthermore, the bionic nanomedicine developed by us has the characteristics of dual drugs delivery, homologous tumor targeting, and photothermal and chemical synergistic therapy, and is expected to become a potential platform for cancer treatment.

Gut microbiome-derived butyrate inhibits the immunosuppressive factors PD-L1 and IL-10 in tumor-associated macrophages in gastric cancer

ABSTRACT Early detection and surgical treatment are essential to achieve a good outcome in gastric cancer (GC). Stage IV and recurrent GC have a poor prognosis. Therefore, new treatments for GC are needed. We investigated the intestinal microbiome of GC patients and attempted to reverse the immunosuppression of the immune and cancer cells of GC patients through the modulation of microbiome metabolites. We evaluated the levels of programmed death-ligand 1 (PD-L1) and interleukin (IL)-10 in the peripheral blood immunocytes of GC patients. Cancer tissues were obtained from patients who underwent surgical resection of GC, and stained sections of cancer tissues were visualized via confocal microscopy. The intestinal microbiome was analyzed using stool samples of healthy individuals and GC patients. Patient-derived avatar model was developed by injecting peripheral blood mononuclear cells (PBMCs) from advanced GC (AGC) patients into NSG mice, followed by injection of AGS cells. PD-L1 and IL-10 had higher expression levels in immune cells of GC patients than in those of healthy controls. The levels of immunosuppressive factors were increased in the immune and tumor cells of tumor tissues of GC patients. The abundances of Faecalibacterium and Bifidobacterium in the intestinal flora were lower in GC patients than in healthy individuals. Butyrate, a representative microbiome metabolite, suppressed the expression levels of PD-L1 and IL-10 in immune cells. In addition, the PBMCs of AGC patients showed increased levels of immunosuppressive factors in the avatar mouse model. Butyrate inhibited tumor growth in mice. Restoration of the intestinal microbiome and its metabolic functions inhibit tumor growth and reverse the immunosuppression due to increased PD-L1 and IL-10 levels in PBMCs and tumor cells of GC patients.

The lncRNA CADM2-AS1 promotes gastric cancer metastasis by binding with miR-5047 and activating NOTCH4 translation.

Multi-organ metastasis has been the main cause of death in patients with Gastric cancer (GC). The prognosis for patients with metastasized GC is still very poor. Long noncoding RNAs (lncRNAs) always been reported to be closely related to cancer metastasis. In this paper, the aberrantly expressed lncRNA CADM2-AS1 was identified by lncRNA-sequencing in clinical lymph node metastatic GC tissues. Besides, the role of lncRNA CADM2-AS1 in cancer metastasis was detected by Transwell, Wound healing, Western Blot or other assays in vitro and in vivo. Further mechanism study was performed by RNA FISH, Dual-luciferase reporter assay and RT-qPCR. Finally, the relationship among lncRNA CADM2-AS1, miR-5047 and NOTCH4 in patient tissues was detected by RT-qPCR. In this paper, the aberrantly expressed lncRNA CADM2-AS1 was identified by lncRNA-sequencing in clinical lymph node metastatic GC tissues. Besides, the role of lncRNA CADM2-AS1 in cancer metastasis was detected in vitro and in vivo. The results shown that overexpression of the lncRNA CADM2-AS1 promoted GC metastasis, while knockdown inhibited it. Further mechanism study proved that lncRNA CADM2-AS1 could sponge and silence miR-5047, which targeting mRNA was NOTCH4. Elevated expression of lncRNA CADM2-AS1 facilitate GC metastasis by up-regulating NOTCH4 mRNA level consequently. What's more, the relationship among lncRNA CADM2-AS1, miR-5047 and NOTCH4 was further detected and verified in metastatic GC patient tissues. LncRNA CADM2-AS1 promoted metastasis in GC by targeting the miR-5047/NOTCH4 signaling axis, which may be a potential target for GC metastasis.

Asialoglycoprotein Receptor 2 Expression in Patients With Locally Advanced Gastric Cancer After Curative Resection.

The asialoglycoprotein receptor 2 gene (ASGR2) encodes a subunit of the asialoglycoprotein receptor, a transmembrane protein, which has recently been reported to be involved in gastric cancer (GC) progression. This study aimed to investigate the clinical significance of ASGR2 expression in GC tissues of patients with locally advanced gastric cancer (LAGC) after curative resection. ASGR2 expression was measured in GC tissues and adjacent normal gastric mucosa in 253 patients with pStage II/III GC who underwent curative resection, by using quantitative polymerase chain reaction. We compared the expression levels in GC tissues and adjacent normal stomach mucosa, and evaluated the relationship of its expression in GC tissues with clinicopathological factors and overall survival (OS). ASGR2 expression was significantly associated with lymph node metastasis and venous invasion. The high ASGR2-expression group demonstrated significantly lower survival than the low expression group (5-year survival 55.5% vs. 72.6%; p=0.009). Furthermore, in multivariate analysis, high ASGR2 expression was an independent factor for poor OS (hazard ratio=2.030; 95% confidence interval=1.318-3.127; p=0.001). ASGR2 expression in GC tissues may be a useful prognostic marker in patients with LAGC after curative resection.

Clinical Significance of Pregnancy Zone Protein Expression in Patients With Locally Advanced Gastric Cancer After Curative Resection.

Pregnancy zone protein (PZP), encoded by PZP, belongs to the α-2-macroglobulin superfamily, and plays an important role in inflammatory responses and immune cell activation in cancer. However, the relationship between gastric cancer (GC) and PZP is poorly studied. This study investigated the clinical significance of PZP expression in GC tissues of patients with locally advanced GC after curative resection. Using quantitative polymerase chain reaction, we measured PZP expression in GC tissues and adjacent normal gastric mucosa of 253 patients with pStage II/III GC who underwent curative resection. We compared the expression levels of PZP in GC tissues and adjacent normal gastric mucosa and examined the relationship of PZP expression in GC tissues with clinicopathological factors and overall survival (OS). PZP expression was significantly associated with histology, venous invasion, and pathological stage. The high PZP expression group had significantly worse OS than did the low expression group (5-year survival 48.6% vs. 68.5%, p=0.0003). Furthermore, in multivariate analysis, high PZP expression was an independent factor for poor OS (hazard ratio=1.984, 95% confidence interval=1.307-3.012, p=0.0013). In post-curative resection patients with locally advanced GC, PZP expression in GC tissue may be a useful prognostic marker.

Upregulation of LINC00501 by H3K27 acetylation facilitates gastric cancer metastasis through activating epithelial-mesenchymal transition and angiogenesis.

The molecular mechanism of the significant role of long noncoding RNAs (lncRNAs) in the progression and metastasis of gastric cancer (GC) remains largely elusive. Our objective is to detect overexpressed lncRNA in GC and investigate its role in promoting epithelial-mesenchymal transition and tumour microenvironment remodel. LncRNA differential expression profile in GC was analysed using RNA microarrays. The level of LINC00501 was evaluated in both GC patient tissues and GC cell lines by quantitative reverse transcription PCR and large-scale (n=304) tissue microarray. To explore the biological role and regulatory driver of LINC00501 in GC, various experimental techniques including Chromatin isolation by RNA purification (ChIRP), RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP) assay, dual luciferase assays were performed. Clinically, it was observed that LINC00501 level was abnormal overexpression in GC tissue and was associated with GC progression and distant metastasis. Gain and loss molecular biological experiments suggested that LINC00501, promoted EMT process and angiogenesis of GC. Mechanically, the enrichment of H3K27 acetylation in LINC00501 promoter region contributed to the increase of LINC00501 in GC. LINC00501 transactivated transcription of SLUG, by recruiting hnRNPR to its promoter. The growth of GC was inhibited both in vitro and in vivo by suppressing the level of LINC00501 using pharmacological intervention from the histone acetyltransferase (HAT) inhibitor -C646. This study suggests that LINC00501 promotes GC progression via hnRNPR/SLUG pathway, which indicates a promising biomarker and target for GC.

B7-H3 and CD47 co-expression in gastric cancer is a predictor of poor prognosis and potential targets for future dual-targeting immunotherapy.

Gastric cancer (GC) is one of the most prevalent types of cancer worldwide. B7-H3, an immune checkpoint molecule with promising potential, has been found to be overexpressed in various cancers. CD47 is an anti-phagocytic molecule that interacts with the signal regulatory protein alpha (SIRPα) to affect phagocytes. The relationship between the expression of B7-H3 and CD47, two potential therapeutic targets found in tumor cells, remains unknown. In this study, our objective is to investigate the clinical significance of co-expression of B7-H3 and CD47, as well as the potential therapeutic value of combination therapy in GC. We utilized immunohistochemistry (IHC) to assess the expression of B7-H3, CD47, CD68, CD86 and CD163 in tissue microarrays obtained from 268 GC patients who underwent surgeries. Western blotting was employed to assess the protein level of B7-H3 and CD47 in GC tissues. The co-localization of B7-H3/CD47 and CD68 in GC tissues was determined using multiplex immunohistochemistry (m-IHC). We further verified the relationship between B7-H3/CD47 and macrophage infiltration via flow cytometry. To estimate the clinical outcomes of patients from different subgroups, we employed the Kaplan-Meier curve and the Cox model. Among the 268 GC cases, a total of 180 cases exhibited positive expression of B7-H3, while 122 cases showed positive expression of CD47. In fresh GC clinical tissues, B7-H3 and CD47 protein level was also higher in tumor tissue than in adjacent normal tissue. Remarkably, 91 cases demonstrated co-expression of B7-H3 and CD47. We observed a significant correlation between B7-H3 expression and tumor stage (P = 0.001), differentiation (P = 0.045), and depth (P = 0.003). Additionally, there was a significant association between B7-H3 and CD47 expression (P = 0.018). The percentage of B7-H3 and CD47 double positive cells in fresh GC tumor tissues were elevated compared with control adjacent tissues regardless of CD45- or CD45+ cells (P = 0.0029, P = 0.0012). Patients with high B7-H3 or CD47 expression had significantly lower overall survival (OS) rates compared to those with low expression levels (P = 0.0176 or P = 0.0042). Surprisingly, patients with combined high expression of B7-H3 and CD47 exhibited a considerably worse prognosis than others (P = 0.0007). Univariate analysis revealed that cases with high expression of B7-H3, CD47, or both had significantly higher hazard ratios (HR) than cases with low expression of these markers. Furthermore, the results of multivariate analysis indicated that B7-H3/CD47 co-expression and CD47 expression alone are independent prognostic factors for overall survival. Moreover, significant correlations were observed between B7-H3 and CD68 expression, CD47 and CD68 expression, as well as B7-H3/CD47 co-expression and CD68 expression in GC patients (P < 0.001, P = 0.003, and P < 0.001). Flow cytometry test showed that the percentage of CD68-positive cells but not CD86-positive cells among B7-H3-positive or CD47-positive immune cells in GC tumor tissue was elevated significantly compared with adjacent tissue. Our findings demonstrated a correlation between B7-H3 expression and CD47 expression in GC patient tissues. Co-expression of B7-H3 and CD47 can serve as an indicator of poor prognosis in GC patients. In GC tumor tissue, but not adjacent tissue, B7-H3 and CD47 expression was accompanied with macrophage infiltration.

Dopamine receptors gene overexpression in the microenvironment of invasive gastric cancer and its potential implications.

Gastric cancer (GC) is the fifth most common cancer worldwide and the most commonly diagnosed cancer in Iran. The nervous system provides proximity to tumor cells by releasing neurotransmitters such as dopamine and presenting them to the corresponding receptor-bearing tumors. While nerve fibers infiltrate the tumor microenvironment, little is known about the expression levels of dopamine (DA), dopamine receptors (DRs), and catechol-O-methyltransferase (COMT) in GC patients. DRs and COMT expression were analyzed in 45 peripheral blood mononuclear cells (PBMCs) and 20 paired tumor and adjacent tissue of GC patients by quantitative polymerase chain reaction. DA was measured in plasma specimens using enzyme-linked immunosorbent assay. Protein-protein interaction analysis was carried out to identify GC-related hub genes. Increased expression of DRD1-DRD3 was found in tumor specimens compared with adjacent non-cancerous specimens (P < 0.05). A positive correlation was found between DRD1 and DRD3 expression (P = 0.009); DRD2 and DRD3 expression (P = 0.04). Plasma levels of dopamine were significantly lower in patients (1298 pg/ml) than in controls (4651 pg/ml). DRD1-DRD4 and COMT were up-regulated in PBMCs of patients compared with controls (P < 0.0001). Bioinformatic analyses showed 30 hub genes associated with Protein kinase A and extracellular signal-regulated kinase signaling pathways. The findings indicated dysregulation of DRs and COMT mRNA expression in GC and suggest that the brain- gastrointestinal axis may mediate gastric cancer development. Network analysis revealed that combination treatments could be considered for optimizing and improving the precision treatment of GC.

Cigarette Smoke-Induced Gastric Cancer Cell Exosomes Affected the Fate of Surrounding Normal Cells via the Circ0000670/Wnt/β-Catenin Axis.

Cigarette smoke is a major risk factor for gastric cancer. Exosomes are an important part of intercellular and intra-organ communication systems and can carry circRNA and other components to play a regulatory role in the occurrence and development of gastric cancer. However, it is unclear whether cigarette smoke can affect exosomes and exosomal circRNA to promote the development of gastric cancer. Exosomes secreted by cancer cells promote cancer development by affecting surrounding normal cells. Herein, we aimed to clarify whether the exosomes secreted by cigarette smoke-induced gastric cancer cells can promote the development of gastric cancer by affecting the surrounding gastric mucosal epithelial cells (GES-1). In the present study, we treated gastric cancer cells with cigarette smoke extract for 4 days and demonstrated that cigarette smoke promotes the stemness and EMT of gastric cancer cells and cigarette smoke-induced exosomes promote stemness gene expression, EMT processes and the proliferation of GES-1 cells. We further found that circ0000670 was up-regulated in tissues of gastric cancer patients with smoking history, cigarette smoke-induced gastric cancer cells and their exosomes. Functional assays showed that circ0000670 knockdown inhibited the promoting effects of cigarette smoke-induced exosomes on the stemness and EMT characteristic of GES-1 cells, whereas its overexpression had the opposite effect. In addition, exosomal circ0000670 was found to promote the development of gastric cancer by regulating the Wnt/β-catenin pathway. Our findings indicated that exosomal circ0000670 promotes cigarette smoke-induced gastric cancer development, which might provide a new basis for the treatment of cigarette smoke-related gastric cancer.

Hsa_circ_0079598 acts as a potential diagnostic and prognostic biomarker for gastric cancer

Abstract Objectives The work discussed the expression level circular RNA (circRNA) hsa_circ_0079598 for gastric cancer (GC) patients as well as clinicopathological significance. Methods qRT-PCR was utilized for determining the expression level of hsa_circ_0079598 in GC cell lines, 40 GC tissue pairs and their paracancerous tissue specimens, 60 pairs of preoperative and postoperative plasma specimens of GC patients, 20 plasma specimens of patients with gastric polyps, and 60 plasma specimens of the healthy control group. Besides, the correlation with clinicopathological parameters was analyzed. Tumor indices glycan antigen 199 (CA199), glycan antigen 724 (CA724), and pepsinogen I (PGI) were combined to evaluate their auxiliary diagnostic value. The values of hsa_circ_0079598 in the prognosis of GC patients were analyzed using survival curves. Results The relative expression of hsa_circ_0079598 in the cancerous tissues of GC patients was lower than that of their paracancerous tissues (p=0.004). The relative expression of plasma hsa_circ_0079598 in GC patients was lower than that of the healthy control group (p&lt;0.001) and patients with gastric polyps. Moreover, the relative expression of human gastric epithelial cell lines (GES-1) (p&lt;0.05) was higher than that of hsa_circ_0079598 of HGC-27, AGS, and MGC-803 cancer cell lines in GC cell lines. The total survival time of the high-expression patient group (p=0.040) was higher than that of hsa_circ_0079598 in the low-expression patient group. The expression of hsa_circ_0079598 in patients with the tissues and plasma of GC was related to the differentiated degree of tumors and TNM staging (p&lt;0.05). The auxiliary diagnostic value of hsa_circ_0079598 for GC was analyzed using ROC curves. When GC was distinguished from gastric polyps and the healthy control group, the areas under the ROC curve (AUCs) were 0.856 and 0.930, respectively. Hsa_circ_0079598 combined with tumor indices CA199, CA724, and PGI detection had higher specificity and accuracy than those of a single index. Conclusions Hsa_circ_0079598 was low-expression in cell lines, plasma, and GC tissues, which was related to the progress and prognosis of GC. Hsa_circ_0079598 combined with CA199, CA724, and PGI detection can improve the diagnosis of GC.

Identification of PRTN3 as a novel biomarker for the diagnosis of early gastric cance

Gastric cancer (GC) remains one of the most common types of cancer worldwide and has a high mortality rate. However, tools for the early detection of gastric cancer are still lacking. Isobaric tagging for relative and absolute quantitation (iTRAQ) proteomic assays were conducted to identify and quantify the differentially expressed proteins (DEPs) in the gastric mucosal tissues of GC patients at different stages. Bioinformatics analysis was used to identify the pathways enriched among the DEPs and candidate marker proteins. The expression levels and distribution of candidate proteins were confirmed by parallel reaction monitoring (PRM) analysis. In this study, by using the iTRAQ quantitative proteomic strategy, we identified 727 and 502 DEPs that were upregulated in EGC vs. PGC and EGC vs. NGC, respectively. These DEPs were mainly involved in the innate immune response and RNA binding. PRTN3 was identified as a marker of early gastric cancer by Gene Ontology enrichment analysis. Furthermore, the PRM assay confirmed the significant overexpression of PRTN3 in EGC gastric mucosa compared to PGC and NGC mucosa. Our data demonstrated that PRTN3 in the gastric mucosa could be used as a novel biomarker to identify patients with early gastric cancer via endoscopy. SignificanceGastric cancer remains one of the most common types of cancer worldwide and has a high mortality rate. Patients with progressive gastric cancer and gastroesophageal junction cancer have a poor prognosis, with a 5-year relative survival rate of 6%. Therefore, early detection and diagnosis of gastric cancer is a key step toward improving the survival rate.The present study identified PRTN3 as a marker of early gastric cancer by an iTRAQ quantitative proteomic strategy. The PRM assay confirmed the significant overexpression of PRTN3 in EGC gastric mucosa compared to PGC and NGC mucosa. This study discovered that PRTN3 in the gastric mucosa could be used as a novel biomarker to identify patients with early gastric cancer via endoscopy.

Identification of three metabolic subtypes in gastric cancer and the construction of a metabolic pathway-based risk model that predicts the overall survival of GC patients.

Gastric cancer (GC) is highly heterogeneous and GC patients have low overall survival rates. It is also challenging to predict the prognosis of GC patients. This is partly because little is known about the prognosis-related metabolic pathways in this disease. Hence, our objective was to identify GC subtypes and genes related to prognosis, based on changes in the activity of core metabolic pathways in GC tumor samples. Differences in the activity of metabolic pathways in GC patients were analyzed using Gene Set Variation Analysis (GSVA), leading to the identification of three clinical subtypes by non-negative matrix factorization (NMF). Based on our analysis, subtype 1 showed the best prognosis while subtype 3 exhibited the worst prognosis. Interestingly, we observed marked differences in gene expression between the three subtypes, through which we identified a new evolutionary driver gene, CNBD1. Furthermore, we used 11 metabolism-associated genes identified by LASSO and random forest algorithms to construct a prognostic model and verified our results using qRT-PCR (five matched clinical tissues of GC patients). This model was found to be both effective and robust in the GSE84437 and GSE26253 cohorts, and the results from multivariate Cox regression analyses confirmed that the 11-gene signature was an independent prognostic predictor (p < 0.0001, HR = 2.8, 95% CI 2.1-3.7). The signature was found to be relevant to the infiltration of tumor-associated immune cells. In conclusion, our work identified significant GC prognosis-related metabolic pathways in different GC subtypes and provided new insights into GC-subtype prognostic assessment.

Prognostic Value of the Expression of Myeloid Leukemia Factor 1-Interacting Protein in Gastric Cancer and Its Regulatory Role in Tumor Progression

To investigate the prognostic value of the expression of myeloid leukemia factor 1-interacting protein (MLF1IP) in gastric cancer tissue and its regulatory role in tumor progression. Gene Expression Omnibus (GEO) database was used to analyze the expression level of MLF1IP in tumor tissues of gastric cancer patients. Kaplan-Meier Plotter database was used to analyze the relationship between MLF1IP expression level and patient prognosis. We conducted a retrospective analysis of 108 gastric cancer patients who had undergone radical surgery at our hospital between January 2015 and December 2015. The expression of MLF1IP in gastric cancer tissue and adjacent tissues was examined. We analyzed the relationship between MLF1IP and the clinicopathological parameters of gastric cancer patients and its impact on the long-term prognosis of gastric cancer patients. Univariate and multivariate regression analyses were done to identify the risk factors affecting the long-term prognosis of gastric cancer patients. The assessment value of MLF1IP for long-term prognosis of gastric cancer was analyzed with ROC curve. The effects of MLF1IP on the proliferation, migration, and invasion of gastric cancer cells were analyzed in vitro with gastric cancer cell line (MGC803). A xenograft tumor model was established with nude mice to analyze in vivo the effect of MLF1IP on tumor growth. The results of the gastric cancer cohort GSE29272 of GEO database showed that the expression level of MLF1IP in gastric cancer tissues was significantly higher than that in normal tissues ( P<0.05). Analysis with Kaplan-Meier Plotter database indicated that high MLF1IP expression was correlated with poor prognosis in gastric cancer patients. Immunohistochemical analysis showed that the expression level of MLF1IP in gastric cancer tissues was higher than that in adjacent tissues ( P<0.05). Correlation analysis showed that the MLF1IP level in gastric cancer tissue was positively correlated with Ki67 ( r=0.609, P<0.01), peripheral blood carcinoembryonic antigen (CEA) ( r=0.572, P<0.01) and carbohydrate antigen 19-9 (CA19-9) ( r=0.623, P<0.01). Kaplan-Meier (K-M) survival analysis showed that the 5-year survival rate of patients in the MLF1IP high expression group was significantly lower than that in the MLF1IP low expression group ( P<0.01). Cox regression analysis showed that independent risk factors for 5-year survival after radical gastrectomy for gastric cancer included the expression of MLF1IP ( HR=2.508, 95% CI: 1.259-4.999), CEA≥5 μg/L ( HR=2.171, 95% CI: 1.152-4.092), CA19-9≥37 kU/L ( HR=2.401, 95% CI: 1.094-5.269), and T3-T4 stages ( HR=2.779, 95% CI: 1.049-7.358) and N2-N3 stages ( HR=2.072, 95% CI: 1.100-3.904). ROC analysis showed that the sensitivity, specificity, and accuracy of MLF1IP (the cut-off value was 3.00 relative protein expression level) in assessing the 5-year survival rate after radical gastrectomy for gastric cancer was 75.00%, 76.92%, and 76.2%, respectively ( P<0.05). CCK-8, Transwell assay, and scratch assays showed that in vitro knocking down of MLF1 IP gene expression significantly inhibited the proliferation, migration and invasion of gastric cancer cells. Subcutaneous tumor xenograft experiment in nude mice showed that knocking down MLF1 IP gene significantly inhibited tumor growth. Increased expression of MLF1IP in gastric cancer tissue, which may be involved in the malignant activities of proliferation, migration, and invasion of gastric cancer cells, has a certain predictive value for poor prognosis.

Study of LncRNA BANCR Expression in Tumor Tissues and Adjacent Normal Tissues in Gastric Cancer Patients.

Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in various biological processes, including cancer development and progression. This study aimed to investigate the expression differences of the BRAF-activated non-coding RNA (BANCR) gene in GC tissues compared to adjacent normal tissues. The potential diagnostic significance of BANCR in GC was explored, with the aim of improving diagnostic and therapeutic approaches for this global health burden. Tissue samples from 100 gastric cancer (GC) patients were collected, and BANCR expression was analyzed using quantitative real-time PCR. Correlations between BANCR expression and clinicopathological features were assessed, and its biomarker potential was evaluated. In individuals diagnosed with GC, the expression of BANCR was notably elevated in tumor tissues compared to adjacent normal tissues (P < 0.0001). However, the analysis of gene expression data did not demonstrate any statistically significant correlation between elevated BANCR expression and clinicopathological features. According to the ROC analysis, BANCR demonstrated an AUC of 0.6733 (P < 0.0001), with a sensitivity of 73% and a specificity of 45%. However, further evaluation is required to determine its potential as a biomarker (CI 95% = 0.5992 to 0.7473). The observed upregulation of BANCR in GC tissues implies its potential involvement as an oncogenic lncRNA in GC patients. Furthermore, BANCR may serve as a promising biomarker for identification and treatment of GC.

POSTN Secretion by Extracellular Matrix Cancer-Associated Fibroblasts (eCAFs) Correlates with Poor ICB Response via Macrophage Chemotaxis Activation of Akt Signaling Pathway in Gastric Cancer.

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, but its clinical benefit is limited in advanced gastric cancer (GC). Cancer-associated fibroblasts (CAFs) have been reported to be associated with ICB resistance, but the underlying mechanism has not been fully elucidated. Our previous single-cell RNA-seq analysis of GC revealed that POSTN+FAP+ extracellular matrix CAFs (eCAFs) communicate with macrophages. Here, we evaluated the correlation between eCAFs and ICB response in TCGA-STAD and real-world cohorts. Immune infiltration analysis and correlation analysis were performed to assess the relationship between eCAFs and macrophages. We first confirmed a negative correlation between the abundance of eCAFs and the overall response rate (ORR) to anti-PD-1 treatment in TCGA-STAD and real-world GC cohorts. Overexpression of POSTN in CAFs enhanced macrophage chemotaxis, while POSTN interference showed the opposite effect in vitro and in vivo. Furthermore, the cell density of POSTN+ CAFs was positively correlated with the infiltration level of CD163+ macrophages in GC patient tissues. The results demonstrated that POSTN secreted by CAFs enhances macrophage chemotaxis by activating the Akt signaling pathway in macrophages. Additionally, we found that POSTN+FAP+ eCAFs may exist in multiple solid tumors and are associated with ICB resistance. eCAFs promote macrophage chemotaxis through the secretion of POSTN, thereby leading to ICB resistance. High expression of POSTN is likely to predict a poor response to ICB. POSTN downregulation may be considered as a candidate therapeutic strategy to improve ICB efficacy.

CHD4 promotes acquired chemoresistance and tumor progression by activating the MEK/ERK axis

Chemoresistance remains a major challenge in gastric cancer (GC). Chromodomain helicase DNA-binding protein 4 (CHD4) mediated chromatin remodeling plays critical roles in various tumor types, but its role in chemoresistance in GC remains uncharacterized. CHD4 expression was examined by immunohistochemistry and Western blotting. The role of CHD4 on cell proliferation and chemoresistance of GC was examined in vitro and in vivo. Immunoprecipitation and liquid chromatography-mass spectrometry were used to identify CHD4-binding proteins and a proximity ligation assay was used to explore protein-protein interaction. Chemoresistance is associated with upregulation of CHD4 in the tumor tissues of GC patients. Overexpression of CHD4 increased chemoresistance and cell proliferation. Knockdown of CHD4 induced cell apoptosis and cell cycle arrest. CHD4 mediates the decrease of the intracellular concentration of cisplatin by inducing drug efflux. Additionally, CHD4 promotes the interaction between ERK1/2 and MEK1/2, resulting in continuous activation of MEK/ERK pathway. Knockdown of CHD4 in GC increased sensitivity to chemotherapy and suppressed tumor growth in a mouse xenograft model. This study identifies CHD4 dominated multi-drug efflux as a promising therapeutic target for overcoming acquired chemoresistance in GC.

Gastric cancer stem cell-derived exosomes promoted tobacco smoke-triggered development of gastric cancer by inducing the expression of circ670.

As one of the most common malignant cancers in the world, gastric cancer is caused by mang factors among which tobacco smoke is an important risk factor. Gastric cancer stem cells (GCSCs) and the derived exosomes play a key role in the occurrence and development of gastric cancer, and exosomal circRNA is considered as a new regulatory factor in the development of gastric cancer. However, it is unclear whether tobacco smoke can affect exosomes and their transport circRNAs to promote the development of gastric cancer. Herein, we provided a new insight into tobacco smoke promoting the progression of gastric cancer. In the present study, we demonstrated that tobacco smoke-induced exosomes promoted the spheroidizing ability, stemness genes expression, and epithelial-mesenchymal transition (EMT) process of GCSCs. We further found that hsa-circRNA-000670 (circ670) was up-regulated in tissues of gastric cancer patients with smoking history, tobacco smoke-induced GCSCs, and their exosomes. Functional assays have shown that circ670 knockdown inhibited the stemness and EMT process of GCSCs, whereas circ670 overexpression appeared to have an opposite effect. Our findings indicated that exosomal circ670 promotes the development of tobacco smoke-induced gastric cancer, which may provide insight into the mechanism of tobacco smoke promoting the progression of gastric cancer.

Knockdown of LINC01279 Suppresses Gastric Cancer Proliferation and Migration by Inhibiting PI3K/Akt/mTOR Signaling Pathway.

To explore the functional and molecular mechanism of long noncoding RNA LINC01279 in gastric cancer (GC). The LINC01279 expression in GC and tissues of para-carcinoma was detected by qPCR (real-time fluorescent quantitative PCR), and the association between the LINC01279 expression and clinicopathological features of patients with GC was investigated. The colony formation, CCK-8, transwell assays, and cell cycle detection kit were used for detection of the effect of LINC01279 on GC cell proliferation, cell cycle, colony formation, and invasion. The effect of LINC01279 on PI3K/AKT/mTOR in the GC signaling pathway was identified by the Western blotting technique. The effect of LINC01279 on GC cell proliferation in vivo was evaluated by subcutaneous xenograft tumors in the nude mice. The results of qPCR displayed the expression of LINC01279 was higher in tissues of GC patients. Furthermore, the tumor size, TNM stage, and metastasis of lymph nodes were also closely related to LINC01279 expression. The experiments on cell function showed that the LINC01279 knockdown significantly inhibited the colony formation, invasion, and proliferation of GC cells and induced the cell cycle arrest in G0 and G1 phases. The Western blotting technique also showed that LINC01279 knockdown significantly inhibited the phosphorylation of PI3K, Akt, and mTOR in GC cells. Furthermore, in vivo experiments displayed that the LINC01279 knockdown significantly inhibited the GC growth. Knockdown of LINC01279 plays a significant role in inhibiting the PI3K/AKT/mTOR signaling pathway which affects the GC invasion and proliferation. The LINC01279 expression can be utilized as a biomarker for the prediction of the GC prognosis.

A novel metabolism-related prognostic gene development and validation in gastric cancer.

The importance of metabolism-related alterations in the development of gastric cancer (GC) is increasingly recognized. The present study aimed to identify metabolism-related genes to facilitate prognosis of GC patients. Gene expression datasets and clinical information of GC patients were downloaded from TCGA and GEO databases. We scored the enrichment of human metabolism-related pathways (n = 86) in GC samples by GSV, constructed prognostic risk models using LASSO algorithm and multivariate Cox regression analysis, combined with clinical information to construct a nomogram, and finally cis score algorithm to analyze the abundance of immune-related cells in different subtypes. We used Weka software to screen for prognosis-related marker genes and finally validated the expression of the selected genes in clinical cancer patient tissues. We identified that two GC metabolism-related signatures were strongly associated with OS and the levels of immune cell infiltration. Moreover, a survival prediction model for GC was established based on six GC metabolism-related genes. Time-dependent ROC analysis showed good stability of the risk prediction scoring model. The model was successfully validated in an independent ACRG cohort, and the expression trends of key genes were also verified in the GC tissues of patients. DLX1, LTBP2, FGFR1 and MMP2 were highly expressed in the cluster with poorer prognosis while SLC13A2 and SLCO1B3 were highly expressed in the cluster with better prognosis. We identified a risk predictive score model based on six metabolism-related genes related to survival, which may serve as prognostic indicators and potential therapeutic targets for GC.