Extracellular vesicles in gastric cancer: role of exosomal lncRNA and microRNA as diagnostic and therapeutic targets.

Extracellular vesicles (EVs), including exosomes, play a crucial role in intercellular communication and have emerged as important mediators in the development and progression of gastric cancer. This review discusses the current understanding of the role of EVs, particularly exosomal lncRNA and microRNA, in gastric cancer and their potential as diagnostic and therapeutic targets. Exosomes are small membrane-bound particles secreted by both cancer cells and stromal cells within the tumor microenvironment. They contain various ncRNA and biomolecules, which can be transferred to recipient cells to promote tumor growth and metastasis. In this review, we highlighted the importance of exosomal lncRNA and microRNA in gastric cancer. Exosomal lncRNAs have been shown to regulate gene expression by interacting with transcription factors or chromatin-modifying enzymes, which regulate gene expression by binding to target mRNAs. We also discuss the potential use of exosomal lncRNAs and microRNAs as diagnostic biomarkers for gastric cancer. Exosomes can be isolated from various bodily fluids, including blood, urine, and saliva. They contain specific molecules that reflect the molecular characteristics of the tumor, making them promising candidates for non-invasive diagnostic tests. Finally, the potential of targeting exosomal lncRNAs and microRNAs as a therapeutic strategy for gastric cancer were reviewed as wee. Inhibition of specific molecules within exosomes has been shown to suppress tumor growth and metastasis in preclinical models. In conclusion, this review article provides an overview of the current understanding of the role of exosomal lncRNA and microRNA in gastric cancer. We suggest that further research into these molecules could lead to new diagnostic tools and therapeutic strategies for this deadly disease.

Predictive value of NLR and PLR in response to preoperative chemotherapy and prognosis in locally advanced gastric cancer.

Purpose: Pretreatment neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte (PLR) ratios are markers of systemic inflammation. In patients with locally advanced gastric cancer (GC), the utility of these ratios in predicting tumor regression grade (TRG) after neoadjuvant chemotherapy (NCT) remains unclear. Methods: This retrospective study examined 283 locally advanced GC patients who underwent NCT and radical surgery. The receiver operating characteristic (ROC) curve analysis and the Youden index were applied to identify optimal NLR/PLR cutpoints. The Kaplan-Meier method was used to estimate overall survival (OS) and disease-free survival (DFS). Univariate/multivariate analyses were conducted by the logistic regression method. Results: TRG grade proved significantly worse in patients with high values of both NLR and PLR whether in univariate (OR = 3.457; p = 0.044) or multivariate (OR = 6.876; p = 0.028) analysis. The degree of tumor differentiation was an independent predictive factor for TRG (OR = 2.874; p = 0.037) in multivariate analysis. In the subgroup analyses, NLR predicted OS (p = 0.04) and DFS (p = 0.03) in female patients, whereas PLR was predictive of both OS (p = 0.026) and DFS (p = 0.018) in patients with clinical TNM stage 3 disease and dissected lymph node counts <28. PLR similarly predicted OS in patients <65 years old (p = 0.049), those with positive lymph nodes (p = 0.021), or those with moderate or poorly differentiated tumors (p = 0.049). Conclusion: Pretreatment NLR and PLR together serve to independently predict TRG after NCT and surgery in patients with locally advanced GC. Screening for patients with high NLR and PLR values may allow them to benefit upfront from alternatives to NCT.

CA724 Predicts Tumor Regression Grade in Locally Advanced Gastric Cancer Patients with Neoadjuvant Chemotherapy.

Purpose: Tumor regression grade (TRG) is widely used to evaluate the efficacy of neoadjuvant chemotherapy (NCT) and it is related to many clinicopathological factors. However, whether TRG can be predicted by clinical characteristics is unknown. Methods: 141 locally advanced gastric cancer (GC) patients who underwent NCT and curative operation were retrospectively analyzed. TRG is reevaluated according to the CAP guideline. The values of CA199, CA125 and CA724 before NCT (pre-) and after NCT (post-) were extracted from our database. Survival curves on overall survival (OS) were obtained by Kaplan-Meier method, and differences were analyzed by log-rank test. Associations between categorical variables were explored by chi-square test or Fisher's exact method. Univariable and multivariate analyses were performed by logistic regression model or Cox proportional hazard regression model. Results: TRG was related to OS (P < 0.001), especially when divided into responders (TRG 0-1) and non-responders (TRG 2-3). Pre-CA724 (p = 0.029) and post-CA199 (p = 0.038) were related to OS. In multivariable analysis, pre-CA724 (p = 0.015) and post-CA199 (p = 0.007) were independent prognostic factors for OS, respectively. The changes (diff-) of all tumor markers were not related to OS. Among the clinical characteristics, pre-CA724 (P = 0.047) and tumor size (P = 0.012) were related to TRG, while pre-CA199 (P = 0.377) and pre-CA125 (P = 0.856) were not. In logistics analysis, pre-CA724 (P = 0.032), tumor size (P = 0.011) and tumor location (P = 0.047) were independent risk factors to pathological response. Conclusion: CA724 was an independent prognostic factor for OS and could be used to predict pathological response.

Genome-Scale Analysis Identified NID2, SPARC, and MFAP2 as Prognosis Markers of Overall Survival in Gastric Cancer.

BACKGROUND Gastric cancer is the most common gastrointestinal tumor, and the rates of recurrence and metastasis are high. Research results on molecular biomarkers used for prognosis of gastric cancer remain inconclusive. This study aimed to explore the gene expression module of gastric cancer and to determine potential prognostic biomarkers. MATERIAL AND METHODS Three microarray datasets (GSE13911, GSE79973, and GSE29272) from Gene Expression Omnibus (GEO), including 206 pairs of gastric tumors and adjacent normal samples, were used for analysis of differentially expressed genes (DEGs). The 3 microarray datasets yielded 144 genes associated with the progression and prognosis of gastric cancer. After this, a risk score model was developed for result validation using an independent dataset from The Cancer Genome Atlas. RESULTS The validation of the independent dataset showed significantly increased NID2, SPARC, and MFAP2 expression in gastric tumor tissues, which were associated with poor outcomes in gastric cancer patients. Moreover, the high risk score obtained was associated with poor overall survival (HR: 1.787; 1.069-2.986; P=0.027). Subgroup analyses revealed that these significant prognostic values were detected in patients aged <65.0 years, tumors in the antrum/distal colon, grade 3 tumors, or TNM-M0 stages of cancer. CONCLUSIONS The findings of this study show that NID2, SPARC, and MFAP2 are upregulated in gastric tumor tissues and are significantly associated with poor overall survival. Therefore, the predictive values of the risk score model employed for the prognosis of gastric cancer could be improved by using these 3 upregulated DEGs.

CA724 predicts overall survival in locally advanced gastric cancer patients with neoadjuvant chemotherapy.

BACKGROUND: Serum tumor markers including AFU, AFP, CEA, CA199, CA125 and CA724, are of great importance in the diagnosis, prognostic prediction and recurrence monitoring of gastrointestinal malignancies. However, their significance in gastric cancer (GC) patients with neoadjuvant therapy (NCT) is still uncertain. The aim of this study was to evaluate the predictive value of these six tumor markers in locally advanced GC patients who underwent NCT and curative surgery. METHODS: In total, 290 locally advanced GC patients who underwent NCT and D2 radical gastrectomy were retrospectively analyzed. Data on their tumor markers before (pre-) and after (post-) NCT and pathological characteristics were extracted from the database of our hospital. The optimal cutoff values of the six tumor markers were calculated by the ROC curve and Youden index. Their predictive significance was analyzed and survival curves for overall survival (OS) were obtained by the Kaplan-Meier method. Associations between categorical variables were explored by the chi-square test or Fisher's exact test. Multivariate analyses were performed by the Cox regression model. RESULTS: Pre- and post-CA199, -CA125 and -CA724 could predict overall survival (all P < 0.05), but only the change (diff-) of CA199 was related to prognosis (P = 0.05). In the multivariable analysis, pre- (P = 0.014) and post-CA724 (P = 0.036) remained significant, though diff-CA724 was not an independent prognostic factor (P = 0.581). In addition, pre- and post-CA199, -CA125 and -CA724 were associated with lymph node metastasis (N- vs N+) and pathological stage (I-II vs III) (all P < 0.05). Moreover, post-CA724 was related to the vascular or lymphatic invasion (P = 0.019), while pre-CA724 was not (P = 0.082). However, AFU, AFP and CEA showed no association with survival (P > 0.05). CONCLUSIONS: CA724 is an independent factor for prognosis and could be used to predict ypN and ypTNM stage in locally advanced GC patients undergoing NCT and curative resection.

Evaluation and Comparison of Predictive Value of Tumor Regression Grades according to Mandard and Becker in Locally Advanced Gastric Adenocarcinoma.

PURPOSE: Tumor regression grade (TRG) has been widely used in gastrointestinal carcinoma to assess pathological responses to neoadjuvant chemotherapy (NCT). There are various standards without a consensus, and it is still unclear which kind of system has better predictive value. This study aims to investigate and compare the predictive ability of the Mandard and Becker TRGs in patients with locally advanced gastric cancer. MATERIALS AND METHODS: A total of 290 patients with locally advanced gastric adenocarcinoma who underwent NCT and curative surgery were studied. Survival analysis for overall survival (OS) and disease-free survival (DFS) were based on the Kaplan-Meier method and Cox proportional hazards method. Predictive values of TRGs and models were assessed by time-dependent receiver operating characteristic (ROC) curve, the area under the ROC curve (AUC), nomogram, and calibration curve. RESULTS: In multivariable analysis, the Mandard TRG was associated with OS (hazard ratio [HR], 1.806; p=0.026) and DFS (HR, 1.792; p=0.017). The Becker TRG was also related to OS (HR, 1.880; p=0.014) and DFS (HR, 1.919; p=0.006). The Mandard and Becker TRG AUCs for 5-year survival were 0.72 and 0.71, respectively. The whole models showed an increased predictive value, with AUCs of 0.85 and 0.86, respectively. There was no significant difference between the two TRGs and two models. CONCLUSION: TRG was an independent predictor for survival, and there was no significant difference between these two systems.

Tumor Regression Grade Predicts Survival in Locally Advanced Gastric Adenocarcinoma Patients with Lymph Node Metastasis.

BACKGROUND: Tumor regression grade (TRG) is widely used in gastrointestinal carcinoma to evaluate pathological responses to neoadjuvant chemotherapy (NCT), but whether it is an independent prognostic factor is still controversial. The aim of this study is to investigate the value of TRG in locally advanced gastric adenocarcinoma patients who underwent NCT and curative resection. METHODS: Pathological regression was reevaluated according to the Mandard TRG. Survival curves were obtained by the Kaplan-Meier method, and differences in overall survival (OS) and disease-free survival (DFS) were compared using the log-rank test. Univariate and multivariate analyses for survival were based on the Cox proportional hazards method. RESULTS: In total, 290 patients were identified in our electronic database. In univariable analysis, TRG was associated with OS (HR = 3.822, P ≤ 0.001) and DFS (HR = 3.374, P ≤ 0.001). However, in multivariable analysis, TRG was not an independent factor for OS (P = 0.231) or DFS (P = 0.191). In the stratified analysis, TRG retrieved prognostic significance in patients with the metastasis of lymph node (HR = 2.034, P = 0.035 for OS; HR = 2.220, P = 0.016 for DFS), while not in patients with negative lymph node (P = 0.296 for OS; P = 0.172 for DFS). CONCLUSIONS: TRG was not an independent predictor for survival, but the system regained its predicting significance in patients with lymph node metastasis.

Identification of the Prognosis-Related lncRNAs and Genes in Gastric Cancer.

Gastric cancer is a common malignant tumor with high occurrence and recurrence and is the leading cause of death worldwide. However, the prognostic value of protein-coding and non-coding RNAs in stage III gastric cancer has not been systematically analyzed. In this study, using TCGA data, we identified 585 long noncoding RNAs (lncRNAs) and 927 protein-coding genes (PCGs) correlated with the overall survival rate of gastric cancer. Functional enrichment analysis revealed that the prognostic genes positively correlated with death rates were enriched in pathways, including gap junction, focal adhesion, cell adhesion molecules (CAMs), and neuroactive ligand-receptor interaction, that are involved in the tumor microenvironment and cell-cell communications, suggesting that their dysregulation may promote the tumor progression. To evaluate the performance of the prognostic genes in risk prediction, we built three multivariable Cox models based on prognostic genes selected from the prognostic PCGs and lncRNAs. The performance of the three models based on features from only PCGs or lncRNAs or from all prognostic genes were systematically compared, which revealed that the features selected from all the prognostic genes showed higher performance than the features selected only from lncRNAs or PCGs. Furthermore, the multivariable Cox regression analysis revealed that the stratification with the highest performance was an independent prognostic factor in stage III gastric cancer. In addition, we explored the underlying mechanism of the prognostic lncRNAs in the Cox model by predicting the lncRNA and protein interaction. Specifically, CTD-2218G20.2 was predicted to interact with PSG4, PSG5, and PSG7, which could also interact with cancer-related proteins, including KISS1, TIMP2, MMP11, IGFBP1, EGFR, and CDKN1C, suggesting that CTD-2218G20.2 might participate in the cancer progression via these cancer-related proteins. In summary, the systematic analysis of the prognostic lncRNAs and PCGs was of great importance to the understanding of the progression of stage III gastric cancer.

LncRNA LINC01116 Promotes Cancer Cell Proliferation, Migration And Invasion In Gastric Cancer By Positively Interacting With lncRNA CASC11.

PURPOSE: The oncogenic roles of lncRNA LINC01116 have been reported in several types of cancer, while its involvement in gastric cancer is unknown. This study aimed to investigate the involvement of LINC01116 in gastric cancer. METHODS: Gene expression was detected by qPCR. Correlations were analyzed by linear regression. Overexpression and siRNA silencing techniques were used to analyze gene functions. Cell invasion and migration were analyzed by Transwell assays. RESULTS: LINC01116 and lncRNA CASC11 were both upregulated in cancer tissues compared to cancer-adjacent tissues. Expression levels of LINC01116 and CASC11 were increased with the increase in clinical stages. Expression levels of LINC01116 and CASC11 were positively correlated. Overexpression of LINC01116 mediated the upregulated CASC11 in gastric cancer cells, and CASC11 overexpression also led to overexpressed LINC01116. Overexpression of LINC01116 and CASC11 led to promoted invasion and migration of gastric cancer cells. Rescue experiments showed that CASC11 knockdown attenuated the effects of LINC01116 overexpression. Overexpression of LINC01116 failed to significantly affect cancer cell proliferation. CONCLUSION: LINC01116 promoted cancer cell invasion and migration in gastric cancer by positively interacting with CASC11.