Expression In Gastric Cancer Research Articles

Characterization of NY-ESO-1 gene expression in gastric cancer (GC).

4046 Background: Tumor specific antigens, such as NY-ESO-1 , are emerging as key tumor immune modulating factors with great potential to be used as therapeutic targets to enhance immunotherapy efficacy and expand treatment options for GC. We sought to compare GC tumors expressing high vs low levels of NY-ESO-1 in terms of immune cell abundance in the tumor microenvironment (TME) as well as distinct molecular features and immune biomarkers. Methods: 1967 tumor samples tested with NextGen Sequencing on DNA (592 genes or WES) and RNA (WTS) by Caris Life Sciences (Phoenix, AZ) were retrospectively reviewed. The top quartile of transcripts per million was considered high while the bottom quartile was considered low NY-ISO-1 expression. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutations. Mismatch repair deficiency/microsatellite instability (dMMR/MSI) status was evaluated by a combination of IHC, fragment analysis and NGS of known MSI loci. Gene fusions were detected based on WTS. X2, Fisher-exact, and Mann Whitney tests were used for comparison and significance adjusted for multiple testing by Benjamini-Hochberg correction ( q < 0.05). Cell infiltration in the TME was estimated by quanTIseq. Gene expression profiles were analyzed for a transcriptional signature predictive of response to immunotherapy (T cell-inflamed signature: TIS). Results: The analysis was focused on primary tumors (N = 1323) in this initial study. Expression of NY-ESO-1 was lower in primary/local than metastases (Fold Change FC met vs primary: 1.60, q < 0.05). NY-ESO-1 expression did not appear to be strongly associated with distinct gene mutation profiles in GC. There were no significant differences between low and high expression of NY-ESO-1 with regards to well established immuno-oncology markers (dMMR/MSI, TMB, PD-L1). However, high NY-ESO-1 expression was positively associated with immune related gene expression including CD274, CD80, CD86, CTLA4, HAVCR2, IDO1, IFNG, LAG3, PDCD1, and PDCD1LG2 (FC low vs high: 0.56 to 0.79, q < 0.0001). High NY-ESO-1 expression was also positively associated with cell abundance in the TME including NK cells (FC = 0.87, q < 0.0001), monocytes (FC = 0.29, q < 0.05), myeloid dendritic cells (FC = 0.66, q < 0.0001), CD4+ non-reg T cells (FC = 0.54, q < 0.0001), and CD8+ T cells (FC = 0.73, q < 0.05). Similarly, tumors with high NY-ESO-1 expression were associated with higher TIS scores ( q < 0.0001). Conclusions: In our large cohort of GC, tumors expressing high NY-ESO-1 displayed a distinct landscape of immune cells in the TME and were associated with high expression of immune related genes, as well as high TIS score, which has been reported to predict benefit from anti-PD-1 treatment. The results of our analysis support an association between a more immunologically active tumor microenvironment and NY-ESO-1 gene expression which may have relevant implications on immunotherapy treatment for GC.

Epigenetic modification facilitates proline synthase PYCR1 aberrant expression in gastric cancer

Background & aimsPyrroline-5-carboxylate reductase 1 (PYCR1) upregulation contributes to the progression of gastric cancer (GC) and indicates poor survival. However, PYCR1 expression profile in GC subtypes and the mechanism behind its upregulation are not well-studied. MethodsPYCR1 expression profiles in GC subtypes and different stages of gastric carcinogenesis were assessed in different GC cohorts. Genetic alterations and epigenetic modulation in PYCR1 regulation were further investigated using bioinformatics analysis and in vitro experiments. ResultsPYCR1 expression was significantly higher in intestinal-type GC and associated molecular subtypes in TCGA and ACRG GC cohorts. During the cascade of intestinal-type GC, PYCR1 was continuously increased from normal gastric tissues through to atrophic gastritis, to intraepithelial neoplasia, and to GC. Copy number alterations in PYCR1 were associated with PYCR1 transcript expression. One CpG island was observed in PYCR1 promoter region, and the hypomethylation occurred at this region could contribute to PYCR1 transcriptional activation in GC. Besides, H3K27ac combination was found in PYCR1 promoter, and acetyltransferase p300 induced H3K27ac could promote PYCR1 expression in GC. ConclusionsPYCR1 expression varies across GC subtypes, with intestinal-type GC and associated molecular subtypes having the highest expression. Hypomethylation at CpG sites and p300-induced H3K27ac modification within PYCR1 promoter could contribute to maintaining PYCR1 overexpression in GC. These results provide us with a new insight into epigenetic modulation in mitochondrial proline metabolism.

LncRNAs UC.145 and PRKG1-AS1 Determine the Functional Output of DKK1 in Regulating the Wnt Signaling Pathway in Gastric Cancer

Simple SummaryThe long non-coding RNA (lncRNA) UC.145, which is conserved in gastric cancer tissue, is presented as a potential novel biomarker for the diagnosis, prognosis, and prediction of gastric cancer. In this study, we analyzed and correlated UC.145 expression with that of DKK1, an inhibitor of the canonical Wnt pathway involved in various cancers. Furthermore, we provide evidence that UC.145 regulates the expression of DKK1 by directly targeting another lncRNA, PRKG1-AS1. Regulation of the three genes was closely associated with the overall survival of patients with gastric cancer.DKK1 inhibits the canonical Wnt signaling pathway that is known to be involved in various cancers. However, whether DKK1 acts as an oncogene or tumor suppressor gene remains controversial. Furthermore, the DKK1-regulating mechanism in gastric cancer has not yet been defined. The aim of this study was to explore whether the ultraconserved region UC.145 regulates epigenetic changes in DKK1 expression in gastric cancer. Microarray analysis revealed that UC.145 exhibited the highest binding affinity to EZH2, a histone methyltransferase. The effects of UC.145 inactivation were assessed in gastric cancer cell lines using siRNA. The results indicated that UC.145 triggers DKK1 methylation via interaction with EZH2 and is involved in the canonical Wnt signaling pathway. Additionally, interaction between UC.145 and another long non-coding RNA adjacent to DKK1, PRKG1-AS1, induced a synergistic effect on Wnt signaling. The regulation of these three genes was closely associated with patient overall survival. Inactivation of UC.145 induced apoptosis and inhibited the growth and migratory, invasive, and colony-forming abilities of gastric cancer cells. The study findings provide insights into Wnt signaling in gastric cancer and support UC.145 as a potential novel predictive biomarker for the disease.

Sulforaphane Suppresses the Nicotine-Induced Expression of the Matrix Metalloproteinase-9 via Inhibiting ROS-Mediated AP-1 and NF-κB Signaling in Human Gastric Cancer Cells.

Sulforaphane, a natural phytochemical compound found in various cruciferous vegetables, has been discovered to present anti-cancer properties. Matrix metalloproteinase-9 (MMP-9) plays a crucial role in gastric cancer metastasis. However, the role of sulforaphane in MMP-9 expression in gastric cancer is not yet defined. Nicotine, a psychoactive alkaloid found in tobacco, is associated with the development of gastric cancer. Here, we found that sulforaphane suppresses the nicotine-mediated induction of MMP-9 in human gastric cancer cells. We discovered that reactive oxygen species (ROS) and MAPKs (p38 MAPK, Erk1/2) are involved in nicotine-induced MMP-9 expression. AP-1 and NF-κB are the critical transcription factors in MMP-9 expression. ROS/MAPK (p38 MAPK, Erk1/2) and ROS functioned as upstream signaling of AP-1 and NF-κB, respectively. Sulforaphane suppresses the nicotine-induced MMP-9 by inhibiting ROS-mediated MAPK (p38 MAPK, Erk1/2)/AP-1 and ROS-mediated NF-κB signaling axes, which in turn inhibit cell invasion in human gastric cancer AGS cells. Therefore, the current study provides valuable evidence for developing sulforaphane as a new anti-invasion strategy for human gastric cancer therapy.

Identification by Bioinformatics Analysis of Potential Key Genes Related to the Progression and Prognosis of Gastric Cancer.

ObjectiveDespite increasingly sophisticated medical technology, the prognosis of patients with advanced gastric cancer is still not objectively certain. Therefore, it is urgent to identify new diagnostic and prognostic biomarkers. To identify potential critical genes related to gastric cancer’s staging mechanism and to the prognosis of gastric cancer.MethodsDynamic trend analysis was conducted to find genes with similar trends in gastric cancer staging in order to explore the differentially expressed genes in gastric cancer and identify the intersection of the results of the dynamic trend analysis. Functional predictive analysis were performed on the obtained genes to observe the expression of prognostic genes in gastric cancer and in gastric cancer stages as well as the correlation with tumor immune cell infiltration. Gastric cancer samples were collected and sequenced for follow-up analysis based on the results of the Cancer Genome Atlas (TCGA) database analysis.ResultsThe expression of genes enriched in module 0 had a similar trend in gastric cancer staging. 3213 differential genes were screened. A total of 50 intersection genes were obtained among genes with similar trends, of which only 10 genes have prognostic significance in gastric cancer. These 10 genes were correlated with macrophage infiltration in varying degrees. In addition, we found that AGT was significantly abnormally expressed in the results of sample sequencing. AGT was related to the occurrence of gastric cancer and interacted with brd9, golph3, nom1, klhl25, and psmd11.ConclusionAGT has prominent abnormal expression in gastric cancer and may promote gastric cancer progression. This study provides a new direction for further exploring potential biomarkers and molecular targeted gastric cancer therapy.

Silencing of immunoglobulin superfamily containing leucine-rich repeat inhibits gastric cancer cell growth and metastasis by regulating epithelial–mesenchymal transition

ABSTRACT This study aims to investigate the immunoglobulin superfamily containing leucine-rich repeat (ISLR) expression in gastric cancer (GC) and ISLR’s underlying mechanisms regulation of GC progression. Through The Cancer Genome Atlas (TCGA) cohort datasets, we analyzed the ISLR expression in GC tumor tissues and normal tissues. ISLR expression in GC tissues and cells was determined using quantitative real-time polymerase chain reaction. Cell viability, proliferation, migration, and invasion assays were performed in GC cells transfected with sh-ISLR, ISLR plasmids, or controls. TCGA results showed that ISLR expression was higher in GC tumor tissues compared to normal tissues, and its expression levels were related to lymph node metastasis, tumor size, and clinical stage. ISLR was highly expressed in tumor cells. ISLR knockdown suppressed cell viability, proliferation, migration, and invasion in HGC-27 cells, whereas ISLR overexpression led to opposite effects in AGS cells. Gene Set Enrichment Analysis showed that ISLR could activate the epithelial–mesenchymal transition (EMT) signaling pathway. Silencing of ISLR suppressed EMT in HGC-27 cells and overexpression of ISLR promoted EMT in AGS cells. ISLR was overexpressed in both GC cell lines and tumor tissues, and our study first showed that silencing of ISLR inhibited GC cell growth and metastasis by reversing EMT.

Effect of miR-206 Derived from Bone Marrow Mesenchymal Stem Cells (BMSCs) on CD8 Expression in Gastric Cancer

The BMSCs are one of the components of tumor micro-environment and participate in tumor evolution. Our study aimed to discuss the effect of exosome derived from BMSC on gastric cancer cells. Tumor and para-tumor tissues were isolated to measure miR-206 level by RT-PCR. Gastric cancer cell behaviors were analyzed using MTT assay and scratch test. Gastric cancer model was established and treated TIGIT inhibitor to assess its role in the tumor growth in vivo. The miR-206 in exosome from BMSCs in cancer tissue was detected. CD8 expression excreted by DC could be induced after miR-206 treatment possibly through regulating the signaling pathway of TIGIT/PVR. Inhibition of TIGIT decreased tumor growth, development and reversed tumor phenotype. In conclusion, miR-206 derived from BMSCs induces CD8 expression in gastric cancer through regulating the signaling pathway of TIGIT/PVR, indicating that it might be a novel target for the treatment of gastric cancer.

LINC00839 Promotes the Progression of Gastric Cancer by Sponging miR-1236-3p.

In this paper, LINC00839 expression in gastric cancer (GC) was confirmed by real-time quantitative PCR. The function of LINC00839 in GC was detected by loss of function assays. Luciferase assays was performed to confirm the interaction between LINC00839 and miR-1236-3p. Then we investigated the regulatory effect of LINC00839 on miR-1236-3p. The results confirmed that the expression level of LINC00839 in GC was significantly up-regulated. LINC00839 could promote GC cell proliferation, mobility, and invasion. The detection of luciferase reporter gene confirmed that LINC000839 could bind to the binding site of miR-1236-3p. Our findings suggest that LINC00839 promotes GC progression through sponging miR-1236-3p.

Phosphorylated ATF1 at Thr184 promotes metastasis and regulates MMP2 expression in gastric cancer

BackgroundStudies have revealed an important role of activating transcription factor 1 (ATF1) and phosphorylated ATF1 at Ser63 in tumors. Our previous study identified Thr184 as a novel phosphorylation site of ATF1. However, the role of phosphorylated ATF1 at Thr184 (p-ATF1-T184) in tumor is unclear. This study figured out the role of p-ATF1-T184 in the metastasis of gastric cancer (GC) and in the regulation of Matrix metallopeptidase 2 (MMP2).MethodsImmunohistochemical analysis (IHC) was performed to analyze the level of p-ATF1-T184 and its relationship with clinicopathological characteristics. Wound scratch test, Transwell assay were used to observe the role of p-ATF1-T184 in the invasion and metastasis of GC. The regulation of MMP2 by p-ATF1-T184 was investigated by a series of experiments including quantitative RT-PCR, western blot, gelatin zymography assay, Chromatin immunoprecipitation (ChIP), luciferase reporter assay and cycloheximide experiment. The Cancer Genome Atlas (TCGA) data were used to analyze the expression and prognostic role of ATF1 and MMP2 in GC. Mass spectrometry (MS) following co-immunoprecipitation (co-IP) assay was performed to identify potential upstream kinases that would phosphorylate ATF1 at Thr184.ResultsHigh expression level of p-ATF1-T184 was found and significantly associated with lymph node metastasis and poor survival in a GC cohort of 126 patients. P-ATF1-T184 promoted migration and invasion of gastric cancer cells. Phosphorylation of ATF1-T184 could regulate the mRNA, protein expression and extracellular activity of MMP2. P-ATF1-T184 further increased the DNA binding ability, transcription activity, and stabilized the protein expression of ATF1. Moreover, TCGA data and IHC results suggested that the mRNA level of ATF1 and MMP2, and protein level of p-ATF1-T184 and MMP2 could be prognosis markers of GC. Two protein kinase related genes, LRBA and S100A8, were identified to be correlated with the expression ATF1 in GC.ConclusionOur results indicated that p-ATF1-T184 promoted metastasis of GC by regulating MMP2.

Clinical significance and correlation of miR-200c and P-gp expression in gastric cancer and the effects on multidrug resistance.

Poor prognosis is common in gastric cancer patients due to multidrug resistance (MDR)-induced recurrence and metastasis. In the present study, we investigated the expression of microRNA (miR)-200c in gastric cancer tissues and cell lines and its relationship with the expression of the drug resistant gene ABCB1, which encodes P-glycoprotein (P-gp). The basic characteristics of 102 patients with gastric cancer were reviewed. Real time-polymerase chain reaction (PCR), immunohistochemistry, and Western blot were employed to detect the expression levels of miR-200c and P-gp in gastric carcinoma tissues and cell lines. The correlation of miR-200c messenger RNA (mRNA) level with clinicopathological characteristics and P-gp protein expression were analyzed. SGC7901/vincristine (VCR) cells were transfected with miR-200c mimics or a specific small interfering RNA (siRNA) targeting the ABCB1 gene. The methyl thiazolyl tetrazolium (MTT) assay and flow cytometry were used to determine the role of miR-200c and ABCB1 on the viability and apoptosis of gastric carcinoma cell lines. The level of miR-200c in carcinoma tissues was significantly lower than that in adjacent tissues, and the expression level of P-gp in carcinoma tissues was obviously higher than that in adjacent tissues (P<0.01, P=0.029). The expression levels of miR-200c and P-gp were associated with the malignant characteristics of gastric cancer, and patients with high expression of miR-200c or negative expression of P-gp had a better prognosis (P=0.006, P=0.022). MiR-200c negatively regulated the ABCB1 gene in gastric cancer cell lines. MiR-200c overexpression and ABCB1 down-regulation increased the sensitivity of SGC7901/VCR cells to VCR and reversed MDR by promoting cell apoptosis. The expression level of miR-200c decreases in gastric carcinoma tissues and drug-resistant gastric cancer SGC7901/VCR cells. Overexpression of miR-200c may enhance the sensitivity of SGC7901/VCR cells to VCR by regulating the expression of P-gp.

Differential Expression of Long Noncoding RNA HOTAIR in Intestinal Metaplasia and Gastric Cancer.

INTRODUCTION:High expression of HOTAIR promotes tumor growth and carries a dismal prognosis for the patient. We investigated the prognostic value of HOTAIR expression in gastric cancer (GC) and systematically delineate the expression in relation to Helicobacter pylori infection and preneoplastic changes.METHODS:HOTAIR expression was analyzed in surgical paired tissue samples of patients with GC and biopsy samples from patients with atrophic gastritis and/or intestinal metaplasia (AG ± -IM), chronic nonatrophic gastritis, and controls. The cancer genome atlas (TCGA) data were used for validation. HOTAIR expression was evaluated in sera and ascites of patients with GC. Quantitative HOTAIR expression analysis was performed using quantitative polymerase chain reaction, and LINE-1 methylation was assessed by bisulfite pyrosequencing.RESULTS:HOTAIR was more frequently detected in tumor tissues compared with adjacent gastric mucosa (65.4% vs 8.6%). HOTAIR expression was associated with depth of tumor invasion and tumor location and with shorter overall survival in patients with diffuse-type GC as confirmed in the TCGA cohort. HOTAIR was not detectable in controls but was found in 2.2% of patients with chronic nonatrophic gastritis and 18.3% of patients with AG ± IM, which was further associated with IM, grade of IM, and H. pylori positivity.DISCUSSION:HOTAIR expression was associated with GC and preneoplastic changes of stomach mucosa. Although HOTAIR expression was strongly linked to IM, HOTAIR expression was only associated with worse prognosis in Lauren diffuse and not intestinal type of GC. Further studies are needed to evaluate the value of HOTAIR as diagnostic and predictive biomarker in IM and translational therapeutic relevance of HOTAIR in diffuse-type GC.

Investigating the Prognostic Significance of Pyroptosis-Related Genes in Gastric Cancer and Their Impact on Cells' Biological Functions.

ObjectiveTo probe into the role of pyroptosis-related genes in gastric cancer.MethodsTo establish pyroptosis-related genes, observe their expression in gastric cancer, and analyze the prognosis of pyroptosis-related genes in gastric cancer by single-factor COX, which showed that only GSDME had prognostic significance in gastric cancer. The mRNA expression profiles and lncRNA expression profiles of gastric cancer downloaded from the Cancer Genome Atlas were combined for weighted gene regulatory network analysis, after which the lncRNA nodes of the module to which GSDME belongs were extracted to obtain the lncRNAs−GSDME interactions, which were visualized with Cytoscape network plots. Finally, the effects of GSDME on the proliferation, migration, and apoptosis of gastric cancer cells were observed with CCK8, and flow cytometry.ResultsOur results show that only GSDME has prognostic significance in gastric cancer, and show that it has an important role in a variety of tumors. In addition, our results show that 16 lncRNAs have a significant interaction with GSDME. Finally, the experimental analysis showed that knocking down the expression level of GSDME could affect the growth as well as apoptosis of gastric cancer cells.ConclusionThe significant prognostic significance of GSDME in gastric cancer and the fact that affecting GSDME expression inhibits gastric cancer cell growth suggest that GSDME can be used as a predictive biomarker.

Development and comparison of three 89Zr-labeled anti-CLDN18.2 antibodies to noninvasively evaluate CLDN18.2 expression in gastric cancer: a preclinical study.

Isoform 2 of claudin 18 (CLDN18.2) is overexpressed in gastric cancer and may be a promising imaging target. In this study, we constructed three anti-CLDN18.2 antibodies and compared them in preclinical experiments. Screening from anti-CLDN18.2 nanobody library, we constructed three antibodies, anti-CLDN18.2 VHH (recombinant single-chain antibody fused with poly-histidine-tag), anti-CLDN18.2 VHH-ABD (recombinant single-chain antibody fused fused with albumin binding domain), and anti-CLDN18.2 VHH-Fc (recombinant single-chain antibody fused with IgG1-Fc) and radiolabeled with 89Zr. Affinity assay, in vitro stability, immunoactivity, blood pharmacokinetics, in vivo and ex vivo biodistribution study, specificity study, and immunohistochemical analysis were performed to assess these radiotracers. The EC50 were 12.21nM, 2.48nM, and 0.14nM for anti-CLDN18.2 VHH, anti-CLDN18.2 VHH-ABD, and anti-CLDN18.2 VHH-Fc, respectively. 89Zr-anti-CLDN18.2 VHH demonstrated the lowest tumor uptake in PET imaging. Both 89Zr-anti-CLDN18.2 VHH-ABD and 89Zr-anti-CLDN18.2 VHH-Fc demonstrated high tumor accumulation, with highest ID%/g of 25.78 ± 5.60 at 24h post-injection with 89Zr-anti-CLDN18.2 VHH-ABD and 49.43 ± 9.86 at 72h post-injection with 89Zr-anti-CLDN18.2 VHH-Fc. The specificity of 89Zr-anti-CLDN18.2 VHH-Fc targeting CLDN18.2 was further confirmed by blocking study. The ex vivo biodistribution results were consistent with in vivo biodistribution data. For 89Zr-anti-CLDN18.2 VHH-ABD, tumor uptake was 21.46 ± 1.78 ID%/g at 12h and 13.73 ± 2.22 ID%/g at 108h. For 89Zr-anti-CLDN18.2 VHH-Fc, the tumor accumulation was 25.28 ± 3.83 ID%/g at 12h and 40.13 ± 9.50 ID%/g at 108h. Immunohistochemistry of the xenograft tissue revealed high and homogenous CLDN18.2 expression in CO-SNU620 tumor. Both anti-CLDN18.2 VHH-ABD and anti-CLDN18.2 VHH-Fc can be efficiently and stably radiolabeled with 89Zr for noninvasive imaging and quantification of CLDN18.2 expression in gastric cancer, of which 89Zr-anti-CLDN18.2 VHH-ABD seems to be the optimal choice balancing tumor uptake and liver background. They can provide essential information to select patients who are likely to benefit from CLDN18.2-targeted treatment.

Loss of ARID1A expression is associated with systemic inflammation markers and has important prognostic significance in gastric cancer.

The tumor suppressor gene AT-rich interactive domain 1A (ARID1A) and systemic inflammatory response (SIR) have been reported to be related to the sensitivity to immunotherapy. This study intended to explore the relationship between ARID1A expression and SIR, and to further elucidate the prognostic value of ARID1A expression in gastric cancer (GC). The mRNA and protein expression of ARID1A were detected in 272 formalin-fixed paraffin-embedded (FFPE) tumor tissues. The data of nine systemic inflammation markers were collected 1 week before gastrectomy. Univariate and multivariate COX analysis were used to screen out independent predictors of GC. Negative expression of ARID1A protein was related to GC with deficient mismatch repair (dMMR) (p = 0.033), positive programmed cell death-ligand 1 (PD-L1) (p = 0.005) and lower albumin level (p = 0.0064). Low expression of ARID1A mRNA was common in GC with abnormal E-cadherin (p = 0.020) and a higher platelet/lymphocyte ratio (PLR) (p = 0.0391). Multivariate COX analysis showed that the expression of ARID1A protein (p = 0.023), age (p = 0.004), T stage (p = 0.009) and N stage (p = 0.009) were independent predictors of GC. The nomogram established by independent predictors can accurately evaluate the survival risk of patients with GC. The loss of ARID1A protein expression was associated with the dMMR subtype and high expression of PD-L1 in GC. Negative ARID1A protein and low expression of mRNA were associated with aberrant systemic inflammatory markers. The expression of ARID1A protein had important prognostic significance in GC.

The promoter methylation drives down-regulation mode of HIC1 in gastric cancer, its molecular characteristics and downstream functional pathways

Gastric cancer is a common malignant tumor of the gastrointestinal tract with a high incidence and mortality rate. Previous results have suggested that the HIC1 gene might be a tumor suppressor candidate in gastric cancer. However, several critical points need to be elucidated: (1) The correlation of HIC1 promoter methylation with its specific expression level in gastric cancer; (2) The molecular characterization of HIC1 promoter methylation; (3) The possible mechanism by which HIC1 performs its inhibitory role in gastric cancer. To address these questions, we retrieved data from TCGA database to analyze HIC1 promoter methylation levels and transcript expression data, and performed targeted region bisulfite sequencing on three stable HIC1 down-regulated cell lines and normal control cell lines, and performed whole transcriptome and metabolite assays in HIC1 knockout cell lines by CRISPR-Cas9 technique. Results demonstrated that HIC1 promoter hypermethylation might be a crucial driving force leading to its down-regulation in HIC1 expression in gastric cancer. This implicated that promoter CG methylation of HIC1 might play a major role in the development of gastric carcinogenesis. Besides, HIC1 may suppress gastric cancer progression by maintaining the normal cellular metabolism, and inhibiting the mTOR signaling pathway activity.

Relationship between HSP90 protein expression and overall survival and clinicopathological outcomes in gastric cancer patients

&lt;br&gt;&lt;b&gt;Aim:&lt;/b&gt; Gastric cancer is a highly prevalent public health problem with high morbidity and mortality. İts primary treatment is surgery. Recently, studies involving biological parameters and genetics in gastric cancer have been emerging but with many blind spots. Our study aims to investigate the clinicopathological and prognostic significance of heat shock proteins (HSP90) expression in patients with resectable gastric cancer.&lt;/br&gt; &lt;br&gt;&lt;b&gt;Methods:&lt;/b&gt; Single-center retrospective clinical study conducted at the General Surgery Department of the local training and research hospital. Our study involves 54 patients who had curative surgery for gastric cancer between 2011 and 2014.&lt;/br&gt; &lt;br&gt;&lt;b&gt;Results:&lt;/b&gt; Pathological specimens fixed in formalin and paraffin were re-evaluated with HSP90 staining and expression of HSP90 was evaluated. It was found that only 39 (72.2%) patients showed HSP90 expression. Seventeen (31.5%) of those showed mild, 13 (24.1%) had moderate, and 9 (10.5%) severe expression. HSP90 expression did not have a significant effect on survival in patients who underwent curative resection for gastric cancer, although statistically close. The effect of expression and intensity on overall survival was not statistically significant either.&lt;/br&gt; &lt;br&gt;&lt;b&gt;Conclusions:&lt;/b&gt; There are various reports in literature on HSP90 expression in gastric cancer – some find it to be a prognostic factor, some not. There is a number of limitations of our study as we did not include metastatic tumors, the number of patients was low, the study involved only our patients and a single pathologist. This is the first study carried out in our population on this subject. Further studies could be done to evaluate this particular relationship in an effort to possibly identify novel treatments in gastric cancer.&lt;/br&gt;

Systematic analysis of gene expression alteration of BIRC5/survivn in gastric cancer.

353 Background: BIRC5/survivin gene is a member of the inhibitor of apoptosis (IAP) gene family, which encode negative regulatory proteins that prevent apoptotic cell death. Abnormal BIRC5/survivin expression is associated with carcinogenesis. Methods: We used sequencing data from The Cancer Genome Atlas database，Oncomine database and GTEx database, analyzed BIRC5/survivin expression and gene regulation networks in gastric carcinoma (STAD).Kaplan-Meier plotter database was used to assess the BIRC5/survivin prognostic potential. ULACAN was used to further analyze the relationship between the expression of BIRC5/survivin and the clinical stage of gastric cancer, and the methylation data of the promoter region of BIRC5/survivin. LinkedOmics was used to identify differential gene expression with BIRC5/survivin and to analyze Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. Gene enrichment analysis examined target networks of kinases, miRNAs and transcription factors. We investigated the correlation of BIRC5/survivin expression in gastric cancer with immune infiltration levels from TIMER database and TISID database. Results: We found that BIRC5/survivin is overexpressed in gastric cancer. The patient with high expression of this gene is associated with poor prognosis. The expression of BIRC5/survivin is positive with ERBB2 expression,TMB,MSI,MSH2,MSH6,PMS2.BIRC5/surviving expression is significantly positively correlated to tumor purity and has significant negative correlation with the immune cell infiltration level of B cells,CD8+T cells,CD4+T cells, Macrophage cells, Neutrophil cells and Dendritic cells. BIRC5/survivin expression is significantly positively correlated CD274，LAG3 and PDCD1. Our results show a detailed landscape map of BIRC5/survivin gene mutation in STAD. Our results showed the associations between BIRC5/survivin expression and six immune subtypes: C1 (wound healing); C2 (IFN-gamma dominant);C3 (inflammatory); C4 (lymphocyte depleted); C6 (TGF-b dominant) in STAD. Conclusions: Our results demonstrate that data mining efficiently reveals information about BIRC5/survivin expression and potential regulatory networks in gastric cancer, laying a foundation for further study of the role of BIRC5/survivin in carcinogenesis and tumor immunotherapy.

Onco-miR-21 Promotes Stat3-Dependent Gastric Cancer Progression.

Simple SummaryMicroRNAs (miRNAs) are a class of highly conserved small, non-protein coding RNAs with often-deregulated expression in cancer. miR-21 is a well-studied cancer-associated microRNA which is able to regulate proliferation, apoptosis, and invasion. The aim of this study was to investigate the molecular pathways which govern miR-21 expression in gastric cancer (GC), and to assess the therapeutic benefit of targeting miR-21 function with a small, synthetic miR-21 antagomir. We confirmed that miR-21 expression in a preclinical model of early gastric cancer is dependent on Stat3 downstream of the IL-6 family cytokine-mediated activation of gp130 receptor signaling. Antagomir therapy curbed gastric tumor growth, and restricted epithelial-to-mesenchymal transition and matrix remodeling. Our study established miR-21 as a promising anti-cancer target in GC.MicroRNA-21 (miR-21) is a small, non-coding RNA overexpressed in gastric cancer and many other solid malignancies, where it exhibits both pro-and anti-tumourigenic properties. However, the pathways regulating miR-21 and the consequences of its inhibition in gastric cancer remain incompletely understood. By exploiting the spontaneous Stat3-dependent formation of inflammation-associated gastric tumors in Gp130F/F mice, we functionally established miR-21 as a Stat3-controlled driver of tumor growth and progression. We reconciled our discoveries by identifying several conserved Stat3 binding motifs upstream of the miR-21 gene promoter, and showed that the systemic administration of a miR-21-specific antisense oligonucleotide antagomir reduced the established gastric tumor burden in Gp130F/F mice. We molecularly delineated the therapeutic benefits of miR-21 inhibition with the functional restoration of PTEN in vitro and in vivo, alongside an attenuated epithelial-to-mesenchymal transition and the extracellular matrix remodeling phenotype of tumors. We corroborated our preclinical findings by correlating high STAT3 and miR-21 expression with the reduced survival probability of gastric cancer patients. Collectively, our results provide a molecular framework by which miR-21 mediates inflammation-associated gastric cancer progression, and establish miR-21 as a robust therapeutic target for solid malignancies characterized by excessive Stat3 activity.

Ubiquitin Fusion Degradation 1 like Protein Expression in Gastric Cancer and its Clinical Significance

To investigate the expression of ubiquitin fusion degradation 1 like protein in gastric cancer and its relationship with the clinicopathological characteristics. Analyzed the data of ubiquitin fusion degradation 1 like protein in gastric cancer and normal tissues in the Cancer Genome Atlas database and the University of Alabama Cancer database. The expression of ubiquitin fusion degradation 1 like protein from fresh samples was detected by real-time quantitative polymerase chain reaction and Western blot, the expression of ubiquitin fusion degradation 1 like protein from paraffin samples was detected by immunohistochemistry. Observed the relationship between the expression level of ubiquitin fusion degradation 1 like protein and clinicopathological characteristics of patients. Data from the Cancer Genome Atlas and the University of Alabama Cancer Databases suggested that ubiquitin fusion degradation 1 like protein messenger ribonucleic acid expression in gastric cancer tissues was significantly higher than that in normal gastric tissues (p<0.05); Western blot and real-time fluorescence quantitative polymerase chain reaction confirmed that ubiquitin fusion degradation 1 like protein and messenger ribonucleic acid expression in fresh gastric cancer tissues were significantly higher in adjacent tissues (p<0.05). Immunohistochemistry results showed that 88 cases of gastric cancer had positive protein expression in 71 cases and negative expression in 17 cases. The expression difference of ubiquitin fusion degradation 1 like protein in gastric cancer and non-tumor tissues adjacent to the cancer was statistically significant (p<0.05) and it was significantly correlated with tumor, nodes and metastases stage and differentiation degree (p<0.05). The expression level of ubiquitin fusion degradation 1 like protein in gastric cancer tissues is significantly increasing and associated with disease progression, suggesting ubiquitin fusion degradation 1 like protein may be involved in the development and progression of gastric cancer.

Pathological Correlation of Lymphocyte Cytosolic Protein 1 in Gastric Cancer and its Effect on Tumor Immune Infiltration

To investigate the expression of lymphocyte cytoplasmic protein 1 in plasma and tumor tissues of patients with gastric cancer and to analyze the correlation between lymphocyte cytoplasmic protein 1 and clinicopathological indexes and its effect on tumor immune infiltration. The expression of lymphocyte cytoplasmic protein 1 in plasma samples of 61 patients with gastric cancer who underwent surgery from December 2019 to December 2020 was detected by enzyme-linked immunosorbent assay. The expression of lymphocyte cytoplasmic protein 1 was detected by immunohistochemical staining and western blot. To study the correlation between pathology and lymphocyte cytoplasmic protein 1 expression in gastric cancer and the effect of lymphocyte cytoplasmic protein 1 expression on tumor immune infiltration. The expression of lymphocyte cytoplasmic protein 1 was closely related to the tumor size, differentiation, lymph node metastasis, tumor, nodes and metastases stage and depth of invasion of gastric cancer (p<0.05). After the expression of lymphocyte cytoplasmic protein 1, the migration and infiltration ability of gastric cancer MKN45 cells and BGC823 cells were improved (p<0.05). The expression of lymphocyte cytoplasmic protein 1 is closely related to the pathology of gastric cancer and the high expression of lymphocyte cytoplasmic protein 1 can significantly enhance the immune infiltration ability of gastric cancer and then has the potential of drug therapeutic targets.