Independent Prognostic Factor In Gastric Cancer Research Articles

Identification of a novel prognostic model for gastric cancer utilizing glutamine-related genes

BackgroundGlutamine metabolism presents a promising avenue for cancer prevention and treatment, but the underlying mechanisms in gastric cancer (GC) progression remain elusive. MethodsThe TCGA-STAD and GEO GSE62254 datasets, containing gene expression, clinical information, and survival outcomes of GC, were meticulously examined. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were employed to excavate a key module (MEturquoise), which was used to intersect with glutamine metabolism-related genes (GMRGs) and differentially expressed genes (DEGs) to identify differentially expressed GMRGs (DE-GMRGs). LASSO and Cox Univariate analyses were implemented to determine risk model genes. Correlation of the risk model with clinical parameters, pathways, and tumor immune microenvironments, was analyzed, and its prognostic independence was validated by Cox analyses. Finally, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to validate the expression levels of MYB, LRFN4, LMNB2, and SLC1A5 in GC and para-carcinoma tissue. ResultsThe excavation of 4521 DEGs led to the discovery of the key MEturquoise module, which exhibited robust correlations with GC traits. The intersection analysis identified 42 DE-GMRGs, among which six genes showed consistency. Further LASSO analysis established MYB, LRFN4, LMNB2, and SLC1A5 as pivotal risk model genes. The risk model demonstrated associations with oncogenic and metabolism-related pathways, inversely correlating with responses to immune checkpoint blockade therapies. This risk model, together with “age”, was validated to be an independent prognostic factor for GC. RT-qPCR result indicated that MYB, LRFN4, LMNB2, and SLC1A5 expressions were remarkably up-regulated in GC tissues comparison with para-carcinoma tissue. ConclusionThe present study has generated a novel risk module containing four DE-GMRGs for predicting the prognosis and the response to immune checkpoint blockade treatments for GC. This risk model provides new insights into the involvement of glutamine metabolism in GC, warranting further investigation.

Differentially expressed microRNA in prognosis of gastric cancer with Lauren classification.

Gastric cancer (GC) is one of the most common tumors. There were several classifications of GC recently. The value of Lauren classification in evaluating the prognosis after radical gastrectomy was still unclear and the prognosis of gastric cancer remained relatively poor in the absence of prognostic biomarkers. This study aimed to explore microRNA (miRNA) in the prognosis of GC with different Lauren classification. A retrospective study of 1144patients was performed in this study. Quantificational reverse transcription-PCR (qRT-PCR) was used to examine the expression of miRNAs. Univariate and multivariate analysis were performed to evaluate prognosis value of Lauren classification. Total 1144 GC patients were recruited in this cohort, including 302 diffuse type (26.4%), 436 intestinal type (38.1%) and 406 mixed type (35.5%) GC. Multivariate analysis showed that Lauren classification, patients' age, tumor size, tumor infiltrating depth, vascular nerve infiltrating and metastatic lymph nodes ration were significantly correlated with GC patients' OS and DFS. The miR-141-3p, miR-200b-3p and miR-133a-5p were significantly down-regulated in diffuse type compared to intestinal type GC tissues, the miR-105-5p had significant lower expression in diffuse type compared with intestinal type and mixed type GC tissues. As a consequence of univariate analysis, low miR-141-3p in diffuse type GC showed significant worse OS and DFS than high miR-141-3p. Lauren classification was an independent prognostic factor in GC. MiR-141-3p was an independent prognostic factor and a promising prognostic biomarker in Lauren classification GC.

Characterization of tumor endothelial cells (TEC) in gastric cancer and development of a TEC-based risk signature using single-cell RNA-seq and bulk RNA-seq data.

Tumor endothelial cells (TECs) are essential participants in tumorigenesis. This study is focused on elucidating the TEC traits in gastric cancer (GC) and constructing a prognostic risk model to predict the clinical outcome of GC patients. Single-cell RNA sequencing (scRNA-seq) data were obtained from the GEO database. Using specific markers, the Seurat R package aided in processing scRNA-seq data and identifying TEC clusters. Based on TEC cluster-associated genes identified by Pearson correlation analysis, TEC-related prognostic genes were screened by lasso-Cox regression analysis, thereby constructing a risk signature. A nomogram was created by combining the risk signature with clinicopathological features. Based on the scRNA-seq data, 5 TEC clusters were discovered in GC, with 3 of them showing prognostic associations in GC. A total of 163 genes were pinpointed among 3302 DEGs as significantly linked to TEC clusters, leading to the formulation of a risk signature comprising 8 genes. Furthermore, there was a notable correlation between the risk signature and the immune cell infiltration. Multivariate analysis findings indicated that the risk signature served as an independent prognostic factor for GC. Moreover, its efficacy in forecasting immune response was validated. TEC-based risk model is highly effective in predicting the survival outcomes of GC patients and can forecast the immune response. Targeting TECs may significantly inhibit tumor progression and enhance the efficacy of immunotherapy.

Effects of tumor marker regression load score on long-term prognosis of gastric cancer patients undergoing radical surgery after neoadjuvant chemotherapy

BackgroundThe effects of the dynamics of serum tumor markers (CA72-4, CEA, CA19-9, CA125 and AFP) before and after neoadjuvant chemotherapy (NACT) on the prognosis of gastric cancer(GC) patients remain unclear. MethodsThe training set contained 334 GC patients from Fujian Medical University Union Hospital (FJMUUH) and 113 GC patients in Qinghai University Affiliated Hospital (QhUAH) were used as an external validation set. Tumor marker regression load (ΔTMRL) indicator, including ΔCA72-4, ΔCEA, ΔCA19-9, ΔCA125, and ΔAFP, is defined as [(postNACT marker– preNACT marker)/preNACT marker]. Tumor marker regression load score (TMRLS) consists of ΔCA72-4, ΔCEA and ΔCA125. The predictive performance of the nomogram-TMRLS was evaluated using the area under the receiver operating characteristic(ROC) curve(AUC), decision curve analysis(DCA), and C-index. ResultsPatients from FJMUUH were divided into two groups, TMRLS-low and TMRLS-high, determined by R package maxstat. Survival analysis revealed a higher 3-year overall survival(OS) in the TMRLS-low than in the TMRLS-high group. The TMRLS-high group who received postoperative adjuvant chemotherapy(AC) showed a significantly higher 3-year OS rate than those who did not. Multivariate COX regression analysis indicated that TMRLS was an independent prognostic factor for OS. A nomogram for predicting OS based on TMRLS showed a significantly higher C-index and AUC than the ypTNM stage. The above results were also found in the QhUAH external validation cohort. ConclusionTMRLS is a novel independent prognostic factor for GC who underwent NACT and a radical gastrectomy. Furthermore, the TMRLS-high group, who received postoperative AC, may achieve better survival outcomes. Notably, the predictive performance of the nomogram-TMRLS significantly outperformed that of the ypTNM stage.

CircUSP1 as a novel marker promotes gastric cancer progression via stabilizing HuR to upregulate USP1 and Vimentin

Circular RNAs (circRNAs) play a crucial role in regulating various tumors. However, their biological functions and mechanisms in gastric cancer (GC) have not been well understood. Here, we discovered a stable cytoplasmic circRNA named circUSP1 (hsa_circ_000613) in GC. CircUSP1 upregulation in GC tissues was correlated with tumor size and differentiation. We observed that circUSP1 promoted GC growth and metastasis. Mechanistically, circUSP1 mainly interacted with the RRM1 domain of an RNA-binding protein (RBP) called HuR, stabilizing its protein level by inhibiting β-TrCP-mediated ubiquitination degradation. The oncogenic properties of HuR mediated promotive effects of circUSP1 in GC progression. Moreover, we identified USP1 and Vimentin as downstream targets of HuR in post-transcriptional regulation, mediating the effects of circUSP1. The parent gene USP1 also enhanced the viability and mobility of GC cells. Additionally, tissue-derived circUSP1 could serve as an independent prognostic factor for GC, while plasma-derived circUSP1 showed promise as a diagnostic biomarker, outperforming conventional markers including serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA19-9). Our study highlights that circUSP1 promotes GC progression by binding to and stabilizing oncogenic HuR, thereby facilitating the upregulation of USP1 and Vimentin at the post-transcriptional level. These findings suggest that circUSP1 could be a potential therapeutic target and a diagnostic and prognostic biomarker for GC.

Construction of gastric cancer prognostic signature based on the E26 transcription factor and the identification of novel oncogene ELK3.

The aim of the present study was to investigate the function of 29 E26 (ETS) transcription factor families in gastric cancer (GC) and determine their association with prognosis. Our analysis of the expression of the ETS family revealed that 28 genes were dysregulated in GC, and that their expression was associated with multiple clinicopathological features (P<0.05). Based on the expression signature of the ETS family, consensus clustering was performed to generate two gastric cancer subtypes. These subtypes exhibited differences in overall survival (OS, P = 0.161), disease-free survival (DFS, P<0.05) and GC grade (P<0.01). Functional enrichment analysis of the target genes associated with the ETS family indicated that these genes primarily contribute to functions that facilitate tumor progression. A systematic statistical analysis was used to construct a prognostic model related to OS and DFS in association with the ETS family. This model demonstrated that the maximum area under the curve (AUC) values for predicting OS and DFS were 0.729 and 0.670, respectively, establishing ETS as an independent prognostic factor for GC Furthermore, a nomogram was created from the prognostic signature, and its predictive accuracy was confirmed by a calibration curve. Finally, the expression and prognostic significance of the six genes comprising the model were also examined. Among these, ELK3 was found to be significantly overexpressed in GC clinical samples. Subsequent in vitro and in vivo studies verified that ELK3 regulates GC proliferation and metastasis, highlighting its potential as a therapeutic target for gastric cancer.

Clinical significance of tumor deposits in gastric cancer after radical gastrectomy: a propensity score matching study

ObjectiveThe value of tumor deposits (TDs) in the prognosis and staging of gastric cancer (GC) is still under debate. This study aims to evaluate the prognostic value of TDs and the best ways to incorporate TDs in the TNM classification of GC.MethodsPatients (n = 3460) undergoing curative gastrectomy for GC in the West China Hospital from 2005 to 2017 were retrospectively reviewed and divided into two groups according to the TD status (positive vs. negative). Later, clinicopathological features and overall survival (OS) between the two groups were compared. Thereafter, the associations between the presence of TD and other clinicopathological factors were evaluated through logistic regression. In addition, univariate and multivariate Cox regression were conducted for determining prognostic factors. The possibility of selection bias was reduced through conducting the 1:1 propensity score matching (PSM) analysis. The modified classification systems proposed previously that incorporated TDs into the TNM staging system were assessed.ResultsThere were 10.5% of patients (362/3460) diagnosed with TDs. TDs were significantly related to unfavorable factors such as advanced T stage and N stage and independently associated with poor prognosis. The 5-year OS of patients with TDs was significantly lower than that of patients without TDs (31.0% vs. 60.9%, P < 0.001), whereas higher than that of patients with peritoneal metastasis (31.0% vs. 5.0%, P < 0.001). In patients receiving chemotherapy, the 5-year OS of patients with TDs was also significantly lower than that of patients without TDs (42.0% vs. 50.9%, P = 0.026). Moreover, the system incorporating TDs in the TNM classification as metastatic lymph nodes outperformed others.ConclusionsTDs are related to the aggressive characteristics and are an independent prognostic factor for GC. Incorporating TDs in the TNM classification as the metastatic lymph nodes increases the accuracy in predicting prognosis.

Targeting TLK2 inhibits the progression of gastric cancer by reprogramming amino acid metabolism through the mTOR/ASNS axis.

Several recent studies have suggested that TLKs are related to tumor progression. However, the function and mechanism of action of TLK2 in gastric cancer (GC) remain elusive. In this study, TLK2 was found to be significantly upregulated in patients with GC and was identified as an independent prognostic factor for GC. Consistently, TLK2 knockdown markedly reduced the aggressiveness of GC, whereas its overexpression had the opposite effect. IP-MS revealed that the effects of TLK2 on GC were mainly associated with metabolism reprogramming. TLK2 knockdown suppressed amino acid synthesis by downregulating the mTORC1 pathway and ASNS expression in GC cells. Mechanistically, mTORC1 directly interacts with the ASNS protein and inhibits its degradation. Further experiments validated that the ASNS protein was degraded via ubiquitination instead of autophagy. Inhibiting and activating the mTORC1 pathway can upregulate and downregulate ASNS ubiquitination, respectively, and the mTORC1 pathway can reverse the regulatory effects of TLK2 on ASNS. Furthermore, TLK2 was found to regulate the mRNA expression of ASNS. TLK2 directly interacted with ATF4, a transcription factor of ASNS, and promoted its expression. The kinase inhibitor fostamatinib significantly inhibited the proliferative, invasive, and migratory capabilities of GC cells by inhibiting TLK2 activity. Altogether, this study reveals a novel functional relationship between TLK2 and the mTORC1/ASNS axis in GC. Therefore, TLK2 may serve as a potential therapeutic target for GC.

MGST1 Expression Is Associated with Poor Prognosis, Enhancing the Wnt/β-Catenin Pathway via Regulating AKT and Inhibiting Ferroptosis in Gastric Cancer.

The role of microsomal glutathione S-transferase 1 (MGST1) underlying gastric cancer (GC) is unclear. The purpose of this research was to study the expression level and biological functions of MGST1 in GC cells. Expression of MGST1 was detected by RT-qPCR, Western blot (WB), and immunohistochemical staining. MGST1 was knockdown and overexpression by short hairpin RNA lentivirus in GC cells. Cell proliferation was evaluated by the CCK-8 assay and EDU assay. The cell cycle was detected by flow cytometry. The TOP-Flash reporter assay was used to examine the activity of T-cell factor/lymphoid enhancer factor transcription based on β-catenin. WB was performed to assess the protein levels involved in the cell signaling pathway and ferroptosis. The MAD assay and C11 BODIPY 581/591 lipid peroxidation probe assay were performed to determine the reactive oxygen species lipid level in GC cells. MGST1 expression was upregulated in GC and it was correlated with poor overall survival of GC patients. MGST1 knockdown significantly inhibited GC cell proliferation and cell cycle by regulating the AKT/GSK-3β/β-catenin axis. In addition, we found that MGST1 inhibits ferroptosis in GC cells. These findings suggested that MGST1 played a confirmed role in promoting GC development and serving as a possible independent prognostic factor for GC.

Glycosyltransferase GLT8D1 and GLT8D2 serve as potential prognostic biomarkers correlated with Tumor Immunity in Gastric Cancer

BackgroundGlycosylation involved in various biological function, aberrant glycosylation plays an important role in cancer development and progression. Glycosyltransferase 8 domain containing 1 (GLT8D1) and GLT8D2, as members of the glycosyltransferase family proteins, are associated with transferase activity. However, the association between GLT8D1/2 and gastric cancer (GC) remains unclear. We aimed to investigate the potential prognostic value and oncogenic role of GLT8D1/2 in GC.MethodsThe relationship between GLT8D1/2 and GC was evaluated through comprehensive bioinformatics approaches. A series of factors like gene expression patterns, Kaplan-Meier survival analyses, Cox regression analyses, prognostic nomogram, calibration curves, ROC curves, function enrichment analyses, tumor immunity association, genetic alterations, and DNA methylation were included. Data and statistical analyses were performed using R software (v3.6.3).ResultsBoth GLT8D1 and GLT8D2 expression were significantly upregulated in GC tissues(n = 414) compared with normal tissues(n = 210), and high expression of GLT8D1/2 was remarkably correlated with poor prognosis for GC patients. Cox regression analyses implied that GLT8D1/2 could act as independent prognostic factors in GC. Furthermore, gene function analyses indicated that multiple signaling pathways involving tumor oncogenesis and development enriched, such as mTOR, cell cycle, MAPK, Notch, Hedgehog, FGF, and PI3K-Akt signaling pathways. Moreover, GLT8D1/2 was significantly associated with immune cell infiltration, immune checkpoint genes, and immune regulators TMB/MSI.ConclusionGLT8D1/2 may serve as potential prognostic markers of poor prognosis in GC correlated with tumor immunity. The study provided an insight into identifying potential biomarkers and targets for prognosis, immunotherapy response, and therapy in GC.

Two web-based dynamic prediction models for the diagnosis and prognosis of gastric cancer with bone metastases: evidence from the SEER database.

Our aim was to identify the clinical characteristics and develop and validate diagnostic and prognostic web-based dynamic prediction models for gastric cancer (GC) with bone metastasis (BM) using the SEER database. Our study retrospectively analyzed and extracted the clinical data of patients aged 18-85 years who were diagnosed with gastric cancer between 2010 and 2015 in the SEER database. We randomly divided all patients into a training set and a validation set according to the ratio of 7 to 3. Independent factors were identified using logistic regression and Cox regression analyses. Furthermore, we developed and validated two web-based clinical prediction models. We evaluated the prediction models using the C-index, ROC, calibration curve, and DCA. A total of 23,156 patients with gastric cancer were included in this study, of whom 975 developed bone metastases. Age, site, grade, T stage, N stage, brain metastasis, liver metastasis, and lung metastasis were identified as independent risk factors for the development of BM in GC patients. T stage, surgery, and chemotherapy were identified as independent prognostic factors for GC with BM. The AUCs of the diagnostic nomogram were 0.79 and 0.81 in the training and test sets, respectively. The AUCs of the prognostic nomogram at 6, 9, and 12 months were 0.93, 0.86, 0.78, and 0.65, 0.69, 0.70 in the training and test sets, respectively. The calibration curve and DCA showed good performance of the nomogram. We established two web-based dynamic prediction models in our study. It could be used to predict the risk score and overall survival time of developing bone metastasis in patients with gastric cancer. In addition, we also hope that these two web-based applications will help physicians comprehensively manage gastric cancer patients with bone metastases.

DISC1 as a prognostic biomarker correlated with immune infiltrates in gastric cancer

Multiple mental diseases could arise in people who have the disrupted in schizophrenia 1 (DISC1) gene. However, it was unknown how DISC1 might contribute to the development of tumors and immune responses. We extracted data from the Cancer Genome Atlas (TCGA) and TISIDB databases from stomach adenocarcinoma (STAD) patients, which revealed that DISC1 overexpression was closely associated with tumor histological type (mucinous vs. tubular, OR = 2.860, CI = 1.423–5.872, p = 0.004), as well as tumor stage and grade. Furthermore, the higher the DISC1 expression, the lower the overall 10-year survival rate. Patients with low DISC1 expression had a significantly longer progression-free interval (PFI) and disease-specific survival (DSS) than patients with high DISC1 expression. However, patients with higher DISC1 expression in the T3&T4, N0&N1 and M0 subgroups had poorer prognosis in terms of OS, DSS and PFI, as could be seen in the subgroup survival analysis. Public datasets were used to predict lncRNA-miRNA-DISC1 regulation. DISC1 was significantly up-regulated in GC(gastric cancer), and its expression levels showed a moderate to strong positive correlation with infiltration levels of effector memory T cells (Tem) and central memory T cells (Tcm), and a negative correlation was observed with Th17 cells and NK CD56bright cells. In addition, concomitant with the high expression of the DISC1 gene was a decrease in MHC-I (Major Histocompatibility Complex-I)expression and an increase in MHC-II expression, and altered chemokine expression. The upregulation of CXCL12 and CXCR4 expression could be caused by an increase in DISC1 expression.The above expression variability and correlation suggest a role for DISC1 in regulating tumor immunity in GC. These findings suggest that high expression of DISC1 could be an independent prognostic factor for GC.

A signature of six-hypoxia-related genes to evaluate the tumor immune microenvironment and predict prognosis in gastric cancer

BackgroundHypoxia will trigger a series of immunosuppressive process in tumor microenvironment, leading to the progression in gastric cancer (GC). This research aims to establish a prognostic model made up of hypoxia-risk-related genes in GC.MethodsHypoxic genes were outlined via the protein–protein interaction network. And a prognostic model was developed using univariate cox analysis and lasso regression from data in TCGA. Two independent queues of GEO were used for validation.ResultsWe set up a hypoxic model presented as an independent prognostic factor for GC. And a nomogram combined this model with clinical features can predict OS with great performance. Furthermore, DNA methylation, IHC and cell line analyses validated the expression of hypoxic genes in GC.ConclusionsIn summary, we proposed and verified a hypoxia-risk-related model, which could reflect the immune microenvironment and predict prognosis in GC.

RETRACTED: The heterogeneity of PD-L1 protein in gastric cancer: expression and distribution characteristics

Programmed death receptor ligand 1 (PD-L1) is expressed at different levels in tumour tissues and tumour-infiltrating monocytes (TIMCs). The interpretation of PD-L1 expression in gastric cancer (GC) is more difficult because of its heterogeneity. The PD-L1 immunohistochemistry (IHC) by E1L3N assay was performed in GC tissues. The level and distributed characteristics of PD-L1 expression were observed to illustrate its heterogeneity both in the cancer tissues and TIMCs. The relationship between PD-L1 level and necrotic features of tumor cells, the number of TIMCs, the distribution of tertiary lymphoid tissue (TLS) in the stroma, and other clinicopathological factors were analysed. A Cox regression model was used to assess the prognostic value of PD-L1 expression. Of the 110 GC samples, not only more cases (51/110 cases) could be detected by combined positive score (CPS) for PD-L1 expression compared the other two, tumour positive score (TPS), and mononuclear immune-cell density score (MIDS), but also there were more cases with the high level of PD-L1 expression by CPS, even if with good consistency among them (P < 0.05). The tumour cells with high expression of PD-L1 was prone to show a diffuse distributing, whereas mottled type in the low level. It was noteworthy that the strongly colored tumor cells tended to exhibit a mossy pattern which were distributed along the border between cancer nests and stroma, and the same pattern happened to occur in the positive mesenchymal cells contacting the tumor border, essentially lymphocytes and macrophages. The substantial necrosis in the tumour and the number of TIMCs was analyzed statistically significant correlated with CPS (P < 0.05), while other clinicopathological factors such as histological type, tumour size, invasion depth, TNM stage were uncorrelated. The number and distribution of TLS in the tumour and para-tumoural stroma indirectly affected PD-L1 in GC by associating with the quantity and pattern of TIMCs. Cox regression analysis revealed that the prognosis was poor when PD-L1 was positive. CPS is the best indicator for PD-L1 expression in GC, which tend to be increased expression following a large number of TIMCs and substantial tumour necrosis appeared. Heterogeneity was reflected in the different distributed pattern of PD-L1 expression, especially the mossy-like pantten of the staining tumor cell in the interface between tumour nests and stroma, regardless of the amount and intensity of PD-L1 expression. TLS is valuable for observing microscopic images to influence the quantity and pattern of TIMCs. CPS can be used as an independent prognostic factor for GC.

DUSP5P1 promotes gastric cancer metastasis and platinum drug resistance

We elucidated the functional significance and molecular mechanisms of DUSP5P1 lncRNA (dual specificity phosphatase 5 pseudogene 1) in gastric carcinogenesis. We demonstrated that gastric cancer (GC) patients with high DUSP5P1 expression had shortened survival in two independent cohorts. DUSP5P1 promoted GC cell migration and invasion in vitro and metastasis in vivo. Mechanistically, DUSP5P1 activated ARHGAP5 transcription by directly binding to the promoter of ARHGAP5 with a binding motif of TATGTG. RNA-seq revealed that ARHGAP5 activated focal adhesion and MAPK signaling pathways to promote GC metastasis. DUSP5P1 also dysregulated platinum drug resistance pathway. Consistently, DUSP5P1 overexpression in GC cells antagonized cytotoxic effect of Oxaliplatin, and shDUSP5P1 plus Oxaliplatin exerted synergistic effect on inhibiting GC metastasis in vitro and in vivo. DUSP5P1 depletion also suppressed the growth of platinum drug-resistant PDO models. In conclusion, DUSP5P1 promoted GC metastasis by directly modulating ARHGAP5 expression to activate focal adhesion and MAPK pathways, serves as therapeutic target for platinum drug resistant GC, and is an independent prognostic factor in GC.

Immune-related gene TM4SF18 could promote the metastasis of gastric cancer cells and predict the prognosis of gastric cancer patients.

Gastric cancer (GC) is one of the most common malignancies in the world, and the search for better markers has become one of the challenges today. It has been found that the L6 superfamily regulates the biological functions of numerous tumors, but transmembrane 4 L six family member 18 (TM4SF18) has been rarely reported. We found that TM4SF18 expression is upregulated in GC tissues and cells, which can be effectively diagnosed and dynamically monitored to assess the prognosis of GC patients. Furthermore, knockdown of TM4SF18 effectively inhibited proliferation, migration, and invasion of GC cells, and affected the epithelial-mesenchymal transition process. TM4SF18 was found to be an independent prognostic factor for GC by univariate and multifactorial Cox analyses as well as by establishing nomogram plots. In addition, in TM4SF18 and immune correlation analysis, TM4SF18 expression levels were found to be negatively correlated with most immune cell marker genes and associated with numerous immune cells and immune pathways, resulting in less benefit from treatment with immune checkpoint inhibitors. In summary, we found that TM4SF18 is a promising GC biomarker that promotes the proliferation, migration, and invasion abilities of GC cells, and is associated with immune response.

Prognostic value of lymph node density on cancer staging system for gastric cancer without distal metastasis: a population-based analysis of SEER database

BackgroundAccurate tumor staging is the cornerstone of tumor treatment. Current tumor staging system for gastric cancer (GC) is based on regional positive lymph nodes while ignoring the total number of examined lymph nodes. We aim to assess the prognostic value of lymph node density (LND), the ratio of positive nodes to the total number examined nodes, in GC without distal metastasis.MethodsClinical information of patients with histologically confirmed GC and without distal metastasis was identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. The X-Tile software was used to identify the ideal prognosis-related cutoff point for LND. The prognostic value of LND on cancer-specific survival (CSS) and overall survival (OS) was assessed in Cox regression models. Subgroup analysis stratified by LND was performed on current lymph node staging system to further explore the interaction between LND and current lymph node staging system.ResultsA total of 4281 participants were identified from the SEER database for the final analysis. The optimal prognosis-related cutoff values of LND were calculated as 0.1 and 0.4, and LND was divided into three levels: LND1 (< 0.1), LND2 (> = 0.1, < 0.4), and LND3 (> = 0.4). LND3 was associated with worse CSS and OS in GC patients. Compared to patients with LND1, those with LND2 and LND3 had 2.43 (HR = 2.43, 95% CI 2.09–2.84, P < 0.001) and 4.69 (HR = 4.69, 95% CI 4.02–5.48, P < 0.001) folds increase in mortality in CSS, respectively. Similar results were found in the evaluation of OS in GC patients. Subgroup analysis stratified by LND also found that patients in the same current lymph node stage still had different prognosis due to the different LND levels after adjustment for other prognosis-related covariates (all P values < 0.001).ConclusionLND is an independent prognostic factor for GC without distal metastasis. In the current lymph node staging system, LND has potential value in further accurately classifying GC patients without distal metastasis.

Increased lncRNA AFAP1-AS1 expression predicts poor prognosis in gastric cancer: Evidence from published studies and followed up verification.

The purpose of this study was to clarify the influence of long non-coding RNA actin fiber-associated protein-1 antisense RNA 1 (lncRNA AFAP1-AS1) on the prognosis of gastric cancer (GC). Based on meta-analysis, the association between the expression of AFAP1-AS1 and the prognosis of GC was estimated. GC tissue and non-cancer tissues from 136 patients were determined by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and verified by Gene Expression Profiling Interactive Analysis (GEPIA). Kaplan-Meier and Cox proportional hazards models were conducted to analyze the correlation between AFAP1-AS1 expression and GC prognosis. The pooled analysis from five studies revealed that the AFAP1-AS1 expression was significantly associated with GC overall survival (hazard ratio (HR) = 2.49 and 95% confidence interval (95% CI): 2.02-3.08, p < 0.001). Compared with non-cancer tissues, AFAP1-AS1 expression level of GC tissues were significantly upregulated (p < 0.001), which was confirmed by the results of GEPIA. The area under the receiver-operating characteristic (ROC) curve was 0.893, and the high expression of AFAP1-AS1 was correlated with poor prognosis in patients with GC (p = 0.005). Clinical grade (HR = 1.912, 95% CI: 1.246-2.934, p = 0.003), pathologic tumor node metastasis (pTNM) (HR = 2.393, 95% CI: 1.431-4.033, p = 0.001), log odds of positive lymph nodes (LODDS) (HR = 2.910, 95% CI: 1.787-4.793, p < 0.001) and AFAP1-AS1 expression (HR = 2.393, 95% CI: 1.869-3.064, p < 0.001) were independent prognostic factors for GC revealed by multivariate Cox-regression analysis. This study demonstrated that the AFAP1-AS1 may be a novel biomarker for the diagnosis and prognosis of GC.

Clinical implications of interleukins-31, 32, and 33 in gastric cancer.

BACKGROUNDGastric cancer (GC) is one of the most common malignancies in China with a high morbidity and mortality.AIMTo determine whether interleukin (IL)-31, IL-32, and IL-33 can be used as biomarkers for the detection of GC, via evaluating the correlations between their expression and clinicopathological parameters of GC patients.METHODSTissue array (n = 180) gastric specimens were utilised. IL-31, IL-32, and IL-33 expression in GC and non-GC tissues was detected immunohistochemically. The correlations between IL-31, IL-32, and IL-33 expression in GC and severity of clinicopathological parameters were evaluated. Survival curves were plotted using the Kaplan-Meier method/Cox regression. Circulating IL-31, IL-32, and IL-33 were detected by ELISA.RESULTSWe found that the expression levels of IL-31, IL-32, and IL-33 were all lower in GC than in adjacent non-GC gastric tissues (P < 0.05). IL-33 in peripheral blood of GC patients was significantly lower than that of healthy individuals (1.50 ± 1.11 vs 9.61 ± 8.00 ng/mL, P <0.05). Decreased IL-31, IL-32, and IL-33 in GC were observed in younger patients (< 60 years), and IL-32 and IL-33 were lower in female patients (P < 0.05). Higher IL-32 correlated with a longer survival in two GC subgroups: T4 invasion depth and TNM I-II stage. Univariate/multivariate analysis revealed that IL-32 was an independent prognostic factor for GC in the T4 stage subgroup. Circulating IL-33 was significantly lower in GC patients at TNM stage IV than in healthy people (P < 0.05).CONCLUSIONOur findings may provide new insights into the roles of IL-31, IL-32, and IL-33 in the carcinogenesis of GC and demonstrate their relative usefulness as prognostic markers for GC. The underlying mechanism of IL-31, IL-32, and IL-33 actions in GC should be further explored.

The Ferroptosis Molecular Subtype Reveals Characteristics of the Tumor Microenvironment, Immunotherapeutic Response, and Prognosis in Gastric Cancer

Ferroptosis is a relatively new form of programmed cell death, which can enhance the efficacy of tumor immunotherapy by regulating the tumor microenvironment (TME). In the face of the dilemma of a great difference in the efficacy of immunotherapy for gastric cancer (GC) patients, the exploration of ferroptosis may assist us in predicting immunotherapy efficacy prior to treatment. The potential role of ferroptosis in TME still needs further elucidation. Based on ferroptosis-related genes (FRGs), we systematically evaluated ferroptosis molecular subtypes in gastric cancer. Additionally, the association between these molecular subtypes and the characteristics of TME was examined. A ferroptosis score was constructed to further explore the predictive efficacy of ferroptosis on the immunotherapy response in gastric cancer. There were also 32 other cancers that were evaluated. Three molecular subtypes of ferroptosis in gastric cancer were identified. The three immunophenotypes of tumor immune inflamed, immune excluded, as well as immune desert were mostly in agreement with the TME features of these three subtypes. The individual tumor genetic variation, TME characteristics, immunotherapy response, and prognosis could be assessed by a ferroptosis score. High ferroptosis scores in gastric cancer suggest stromal activation and immunosuppression. It is noted that tumors with a low ferroptosis score are characterized by extensive tumor mutations as well as an immune activation, which are associated with an enhanced immunotherapy response and an improved prognosis. This study reveals that ferroptosis plays an integral role in the regulation of the tumor immune microenvironment. The ferroptosis score may serve as an independent prognostic factor for GC and will deepen our understanding of the TME infiltration mechanisms as well as lead to more rational immunotherapy regimens.