Distant Metastasis Of Gastric Cancer Research Articles

A nomogram combining neutrophil to lymphocyte ratio (NLR) and prognostic nutritional index (PNI) to predict distant metastasis in gastric cancer

In this study, We aim to explore the association between the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune-inflammatory index (SII), lymphocyte to monocyte ratio (LMR) and prognostic nutritional index (PNI) and distant metastasis of gastric cancer and develop an efficient nomogram for screening patients with distant metastasis. A total of 1281 inpatients with gastric cancer were enrolled and divided into the training and validation set.Univariate, Lasso regression and Multivariate Logistic Regression Analysis was used to identify the risk factors of distant metastasis. The independent predictive factors were then enrolled in the nomogram model. The nomogram’s predictive perform and clinical practicality was evaluated by receiver operating characteristics (ROC) curves, calibration curves and decision curve analysis. Multivariate Logistic Regression Analysis identified d-dimer, CA199, CA125, NLR and PNI as independent predictive factors. The area under the curve of our nomogram based on these factors was 0.838 in the training cohort and 0.811 in the validation cohort. The calibration plots and decision curves demonstrated the nomogram’s good predictive performance and clinical practicality in both training and validation cohort. Therefore,our nomogram could be an important tool for clinicians in screening gastric cancer patients with distant metastasis.

MEF2D facilitates liver metastasis of gastric cancer cells through directly inducing H1X under IL-13 stimulation

Liver metastasis is the most common metastatic occurrence in gastric cancer patients, although the precise mechanism behind it remains unclear. Through a combination of proteomics and quantitative RT-PCR, our study has revealed a significant correlation between the upregulation of myocyte enhancer factor-2D (MEF2D) and both distant metastasis and poor prognosis in gastric cancer patients. In mouse models, we observed that overexpressing or knocking down MEF2D in gastric cancer cells respectively promoted or inhibited liver metastasis. Furthermore, our research has demonstrated that MEF2D regulates the transcriptional activation of H1X by binding to the H1X promoter. This regulation leads to the upregulation of H1X, which, in turn, promotes the in vivo metastasis of gastric cancer cells along with the upregulation of the downstream gene β-CATENIN. Additionally, we found that the expression of MEF2D and H1X at both mRNA and protein levels can be induced by the inflammatory factor IL-13, and this induction exhibits a time gradient dependence. In human gastric cancer tissues, the expression of IL13RA1, the receptor for IL-13, positively correlates with the expression of MEF2D and H1X. IL13RA1 has been identified as an intermediate receptor through which IL-13 regulates MEF2D. In conclusion, our findings suggest that MEF2D plays a crucial role in promoting liver metastasis of gastric cancer by upregulating H1X and downstream target β-CATENIN in response to IL-13 stimulation. Targeting MEF2D could therefore be a promising therapeutic strategy for the clinical management of gastric cancer. Statement of significanceMEF2D promotes its transcriptional activation in gastric cancer cells by binding to the H1X promoter and is upregulated by IL-13-IL13RA1, thereby promoting distant metastasis of gastric cancer.

Application of machine learning algorithm in predicting distant metastasis of T1 gastric cancer

Distant metastasis (DM) is relatively uncommon in T1 stage gastric cancer (GC). The aim of this study was to develop and validate a predictive model for DM in stage T1 GC using machine learning (ML) algorithms. Patients with stage T1 GC from 2010 to 2017 were screened from the public Surveillance, Epidemiology and End Results (SEER) database. Meanwhile, we collected patients with stage T1 GC admitted to the Department of Gastrointestinal Surgery of the Second Affiliated Hospital of Nanchang University from 2015 to 2017. We applied seven ML algorithms: logistic regression, random forest (RF), LASSO, support vector machine, k-Nearest Neighbor, Naive Bayesian Model, Artificial Neural Network. Finally, a RF model for DM of T1 GC was developed. The AUC, sensitivity, specificity, F1-score and accuracy were used to evaluate and compare the predictive performance of the RF model with other models. Finally, we performed a prognostic analysis of patients who developed distant metastases. Independent risk factors for prognosis were analysed by univariate and multifactorial regression. K-M curves were used to express differences in survival prognosis for each variable and subvariable. A total of 2698 cases were included in the SEER dataset, 314 with DM, and 107 hospital patients were included, 14 with DM. Age, T-stage, N-stage, tumour size, grade and tumour location were independent risk factors for the development of DM in stage T1 GC. A combined analysis of seven ML algorithms in the training and test sets found that the RF prediction model had the best prediction performance (AUC: 0.941, Accuracy: 0.917, Recall: 0.841, Specificity: 0.927, F1-score: 0.877). The external validation set ROCAUC was 0.750. Meanwhile, survival prognostic analysis showed that surgery (HR = 3.620, 95% CI 2.164–6.065) and adjuvant chemotherapy (HR = 2.637, 95% CI 2.067–3.365) were independent risk factors for survival prognosis in patients with DM from stage T1 GC. Age, T-stage, N-stage, tumour size, grade and tumour location were independent risk factors for the development of DM in stage T1 GC. ML algorithms had shown that RF prediction models had the best predictive efficacy to accurately screen at-risk populations for further clinical screening for metastases. At the same time, aggressive surgery and adjuvant chemotherapy can improve the survival rate of patients with DM.

Simultaneous colonic metastasis of advanced gastric cancer: a case report

BackgroundAlthough distant metastasis in gastric cancer can be present at the time of the initial diagnosis, colonic metastasis is extremely rare. This report describes a case of simultaneous colonic metastasis of advanced gastric cancer.Case presentationThe patient was a 78-year-old woman with nausea and epigastric pain. Upper gastrointestinal endoscopy revealed an advanced invasive ulcerative tumor in the lesser curvature of the stomach extending from the anterior to the middle portion. Colonoscopy revealed a 4-mm polyp-like lesion in the mid-transverse colon; therefore, a polypectomy was performed. Both gastric and colonic tumors showed poorly differentiated adenocarcinoma with signet ring cell carcinoma. After providing informed consent, the patient underwent a total gastrectomy. Histologic examination showed similar morphologic features of both gastric and colonic tumors. Immunohistochemistry staining showed that these tumor cells were positive for cytokeratin (CK) 7 and negative for CK20.ConclusionsThis was an extremely rare case of simultaneous colonic metastasis of advanced gastric cancer. Because missed metastasis can result in a poorer prognosis, we propose a systemic search including colonoscopy for patients with advanced gastric cancer, especially cases involving poorly differentiated adenocarcinoma or signet ring cell carcinoma.

Factors influencing super-long hospital stays in patients undergoing radical gastrectomy in the age of enhanced recovery after surgery

Objective: To obtain experience and generate suggestions for reducing average hospital stays, optimizing perioperative management of patients with gastric cancer and improving utilization of medical resources by analyzing the factors influencing super-long hospital stays in patients undergoing radical gastrectomy in the age of enhanced recovery after surgery (ERAS). Methods: This was a case-control study. Inclusion criteria: (1) pathologically diagnosed gastric adenocarcinoma; (2) radical surgery for gastric cancer; and (3) complete clinicopathologic data. Exclusion criteria: (1) history of upper abdominal surgery; (2) presence of distant metastasis of gastric cancer or other ongoing neoplastic diseases; (3) concurrent chemoradiotherapy; and (4) preoperative gastric cancer-related complications such as obstruction or perforation. The study cohort comprised 285 eligible patients with hospital stays of ≥30 days (super-long hospital stay group). Using propensity score matching in a 1:1 ratio, age, sex, medical insurance, pTNM stage, and extent of surgical resection as matching factors, 285 patients with hospital stays of < 30 days during the same period were selected as the control group (non-long hospital stay group). The primary endpoint was relationship between pre-, intra-, and post-operative characteristics and super-long hospital stays. Clavien-Dindo grade was used to classify complications. Results: Univariate analysis showed that number of comorbidities, number of preoperative consultations, preoperative consultation, inter-departmental transference, operation time, open surgery, blood loss, intensive care unit time, presence of surgical or non-surgical complications, Clavien-Dindo grade of postoperative complications, and reoperation were associated with super-long hospital stays (all P<0.05). Inter-departmental transference (OR=4.876, 95% CI: 1.500-16.731, P<0.001), preoperative consultation time ≥ 3 d (OR=1.758, 95%CI: 1.036-2.733, P=0.034), postoperative surgery-related complications (OR = 6.618, 95%CI: 2.141-20.459, P=0.01), and higher grade of complications (Clavien-Dindo Grade I: OR = 7.176, 95%CI: 1.785-28.884, P<0.001; Clavien-Dindo Grade II: OR = 18.984, 95%CI: 6.286-57.312, P<0.001; Clavien-Dindo Grade III-IV: OR=7.546, 95%CI:1.495-37.952, P=0.014) were independent risk factors for super-long hospital stays. Conclusion: Optimizing preoperative management, enhancing perioperative management, and surgical quality control can reduce the risk of prolonging average hospital stay.

Clinicopathological and prognostic value of lysyl oxidase expression in gastric cancer: a systematic review, meta-analysis and bioinformatic analysis

The association between the expression of Lysyl oxidase (LOX) and its clinicopathological parameters and prognosis in patients with gastric cancer (GC) is still disputed. We performed this meta-analysis and bioinformatics analysis to clarify the relationship between the expression and methylation level of LOX with its clinicopathological parameters and prognostic value. We applied odds ratios with a 95% confidence interval to study the associations between LOX expression and clinicopathological parameters and overall survival (OS) in GC patients. In addition, association analysis of promoter methylation levels and expression of LOX with its prognostic value was performed using the Cancer Genome Atlas (TCGA) and four Gene Expression Omnibus (GEO) datasets. The PRISMA 2020 checklist was used to guide the data extraction and analysis. This meta-analysis includes seven clinical studies with a total of 1435 GC patients. LOX expression was related to lymph node metastasis and tumor distant metastasis in GC patients, but not to gender, tumor differentiation, Lauren classification, or tumor depth of invasion. Patients with GC grouped in high-expression of LOX had a much worse OS than those in low-expression. In addition, TCGA and four GEO datasets with 1279 samples were included in the bioinformatics analysis. The bioinformatics analysis showed that patients with high LOX levels had poor OS; low levels of methylation at some cg sites in the LOX gene were strongly related to poor OS and PFS; and methylation levels of LOX are negatively correlated with advanced tumor stage. The conclusion from comprehensive DNA methylation and gene expression analysis supports LOX as a specific diagnostic and prognosis biomarker in GC. LOX expression was related to lymph node metastasis, tumor distant metastasis and poor prognosis in GC. Low methylation levels were related to advanced tumor stage and poor prognosis in GC. Integrative analysis supports LOX as a specific diagnostic and prognosis biomarker in GC.

Association of multiple tumor markers with newly diagnosed gastric cancer patients: a retrospective study.

BackgroundThe purpose of this paper was to explore the correlation between multiple tumor markers and newly diagnosed gastric cancer.MethodsWe selected 268 newly diagnosed patients with gastric cancer and 209 healthy subjects for correlation research. The detection of multiple tumor markers was based on protein chips and the results were statistically analyzed using SPSS.ResultsWe concluded that gastric cancer was significantly related to gender, age, alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), carbohydrate antigen 199 (CA199), and carbohydrate antigen 242 (CA242) positive levels (P < 0.001). After CA199 and CA242 were stratified by gender, the male odds ratio (OR) was 30.400 and 31.242, respectively, while the female OR was 3.424. After CA125 was stratified by age in patients over 54 years old with gastric cancer, the risk of occurrence in the CA125-positive population was 16.673 times that of the CA125-negative patients. Among patients 54 years old and younger, being CA125-positive was not a risk factor for gastric cancer (P = 0.082). AFP, CEA, CA125, CA199, and CA242 positive levels during the M1 stage were statistically significant when compared with the M0 stage and control group (P < 0.001), but the AFP (P = 0.045) and CA125 (P = 0.752) positive levels were not statistically significant when compared with the M0 stage and control group. The combined detection sensitivity of multiple tumor markers was 44.78%.ConclusionOur research shows that gastric cancer is associated with age, gender, and the positive levels of AFP, CEA, CA125, CA199, and CA242. The positive levels of AFP and CA125 were related to the distant metastasis of gastric cancer. To a certain extent, the combined detection sensitivity can be used for the initial screening of gastric cancer.

CircNR3C1 Alleviates Gastric Cancer Development by Inactivating AKT/mTOR.

Differential level and regulatory effect of circNR3C1 in gastric cancer (GC) were determined. The differential levels of circNR3C1 in clinical samples of GC were determined. The association of circNR3C1 level with pathological indicators of GC was analyzed. After intervening circNR3C1 levels in gastric cancer cells, proliferative and migratory changes were investigated. Furthermore, we measured AKT and mTOR protein levels in GC cells intervened by circNR3C1. Finally, the role of AKT/mTOR in GC cell phenotypes regulated by circNR3C1 was explored. circNR3C1 was markedly lowly expressed in GC cells and tissues. A low level of circNR3C1 predicted high incidences of lymphatic or distant metastasis of GC. Knockdown of circNR3C1 enhanced proliferation and migration abilities in BGC-823 cells, whereas overexpression of circNR3C1 yielded the opposite results in AGS cells. circNR3C1 downregulated mTOR and AKT in GC cells. In addition, induction of the AKT activator could reverse the attenuated proliferative and migratory potentials in GC cells overexpressing circNR3C1. On the contrary, induction of the AKT inhibitor reversed the stimulated malignant phenotypes of GC with circNR3C1 knockdown. circNR3C1 inhibits GC to proliferate and migrate by inactivating the AKT/mTOR signaling. It is also closely linked to GC metastasis.

GABPA protects against gastric cancer deterioration via negatively regulating GPX1.

BackgroundTo explore the anti-cancer role of GABPA in the progression of gastric cancer (GC), and the underlying mechanism.MethodsQuantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the expression pattern of GABPA in 45 pairs of GC and non-tumoral tissues. The relationship between GABPA expression and clinic pathological indicators of GC patients was analyzed. In AGS and SGC-7901 cells overexpressing GABPA, their migratory ability was determined by trans well and wound healing assay. The interaction between GABPA and its downstream target GPX1 was explored by dual-luciferase reporter assay, and their synergistical regulation on GC cell migration was finally elucidated.ResultsGABPA was downregulated in GC tissues in comparison to normal ones. Low level of GABPA predicted high incidences of lymphatic and distant metastasis in GC. Overexpression of GABPA blocked AGS and SGC-7901 cells to migrate. GABPA could target GPX1 via the predicted binding site. GPX1 was upregulated in clinical samples of GC, and negatively correlated to GABPA level. The anticancer effect of GABPA on GC relied on the involvement of GPX1.ConclusionsGABPA is downregulated in GC samples, which can be utilized to predict GC metastasis. Serving as a tumor suppressor, GABPA blocks GC cells to migrate by targeting GPX1.

Current status of diagnosis and treatment of gastric cancer peritoneal metastasis

Peritoneal metastasis is the most common distant metastasis of gastric cancer. As an end-stage event of gastric cancer, patients with peritoneal metastasis often have lost the chance of radical resection, and even after palliative surgical resection, the long-term outcomes are still not satisfactory. In recent years, with the application and promotion of laparoscopic technology, neoadjuvant intraperitoneal and systemic chemotherapy, hyperthermic intraperitoneal chemotherapy and cytoreductive surgery, through perioperative comprehensive treatment strategies by multidisciplinary team, the quality of life and survival of patients with peritoneal metastasis have been significantly improved. Some patients with gastric cancer peritoneal metastasis diagnosed by laparoscopy even get the opportunity to have radical cytoreductive surgery and hyperthermic intraperitoneal chemotherapy after neoadjuvant intraperitoneal and systemic chemotherapy. Taking into account the progress in the treatment of gastric cancer peritoneal metastasis in recent years, this article intends to combine current clinical evidence and to discuss the key issues in the course of clinical diagnosis and treatment of gastric cancer peritoneal implantation and metastasis, including the imaging diagnosis of peritoneal metastasis, laparoscopic examination, evaluation of peritoneal metastasis and comprehensive treatment plan.

Correlation between the overexpression of epidermal growth factor receptor and pathological features of gastric cancer: a meta-analysis.

BackgroundTo evaluate the overexpression of epidermal growth factor receptor (EGFR) and its correlation with pathological features of gastric cancer, so as to provide a theoretical basis for anti-EGFR targeted therapy.MethodsPubMed, Embase, Web of Science, CNKI, Wanfang were used to retrieve literature on EGFR expression and gastric cancer tissues between January 2009 and March 2020 and Stata 15.0 software was used to analyze. Age, gender, degree of differentiation, depth of invasion, lymph node metastasis, distant metastasis and TNM staging were analyzed with odds ratio (OR) and 95% confidence interval (CI).ResultsA total of 17 articles were included, with 4,424 patients with gastric cancer, of which 1,268 patients with EGFR overexpression. EGFR was related to the infiltration depth (OR =3.26, 95% CI: 1.95–5.44); related to lymph node metastasis (OR =2.10, 95% CI: 1.45–3.04); related to distant metastasis (OR =1.96, 95% CI: 1.41–2.72); related to TNM staging (OR =3.98, 95% CI: 2.09–7.59). However, EGFR overexpression is not concerned with age, gender and differentiation.ConclusionsEGFR overexpression has the predictive value for depth of invasion, lymph node metastasis, TNM staging and distant metastasis of gastric cancer, and may be a predictor of adverse prognosis of gastric cancer. Targeted therapy for EGFR may be considered as one of the means of comprehensive treatment for gastric cancer.

Adenosine Generated by Regulatory T Cells Induces CD8+ T Cell Exhaustion in Gastric Cancer through A2aR Pathway.

Background Adenosine, derived from the degradation of ATP via ectonucleotidases CD39 and CD73, is a critical immunosuppressive metabolite in the hypoxic microenvironment of tumor tissue. Adenosine signaling via A2aR can inhibit the antitumor immune response of CD8+ T cells. CD39 and CD73 high-expressing Tregs play a critical role in tumor immune evasion of gastric cancer (GC). The present study investigated the underlying mechanism by which Tregs suppress antitumor immune responses in GC. Materials and Methods Fifty-two GC samples were collected, and the frequency of FoxP3+ Tregs and CD8+ T cells and density ratios of A2aR+/CD8+ T cells, CD39+/FoxP3+ Tregs, and CD73+/FoxP3+ Tregs in GC were assessed with multiplex immunofluorescence. The expression of FoxP3 and A2aR in GC tissues was also detected by the immunoblotting assay. We next investigated the relationship between density of FoxP3+ Tregs, ratio of A2aR+/CD8+ T cells, and clinicopathological parameters. At the same time, Tregs and CD8+ T cells were isolated from peripheral blood of five GC patients, and the antagonists of CD39 and CD73 were used to assess the ability of Tregs to decompose ATP into adenosine. In addition, we cocultured CD8+ T cells and Tregs with antagonists of A2aR and A2bR in order to examine the alterations in immune function of CD8+ T cells. Results The density of both FoxP3+ Tregs and A2aR+/CD8+ T cells was higher in GC tissue compared to peritumoral normal tissue and significantly correlated with the TNM stage, lymph node metastasis, and distant metastasis of GC. The process of Treg hydrolysis of ATP into adenosine was blocked by the antagonists of CD39 and CD73. In addition, Tregs could induce apoptosis and inhibit proliferation of CD8+ T cells, while this effect could be obviously reduced by applying the antagonist of A2aR or A2aR+A2bR. Moreover, IFN-γ, TNF-α, and perforin generated by CD8+ T cells could also be inhibited through the adenosine A2aR pathway. Conclusions The FoxP3+ Tregs and A2aR+/CD8+ T cells were excessively infiltrated in GC tissue. Tregs from GC can decompose ATP to adenosine and in turn induce apoptosis and inhibit the proliferation of CD8+ T cells through the A2aR pathway, further leading to immune escape of GC.

Lysyl oxidase promotes liver metastasis of gastric cancer via facilitating the reciprocal interactions between tumor cells and cancer associated fibroblasts.

BackgroundLiver is one of the most preferred destinations of distant metastasis in gastric cancer (GC). As effective treatment is still limited, the prognosis of GC patients bearing liver metastasis is poor. We filter out lysyl oxidase (LOX) to study its function in the tumor microenvironment (TME) and seek for potential therapeutic targets.MethodsTranscription analysis on 6 cases of liver metastasis of GC patients with respective paired primary tumors and adjacent normal livers was performed. The filtration out of LOX was done using 5 datasets. 69 GC liver metastasis tissues were utilized to perform immunohistochemistry (IHC) and analyze prognosis. Computed Tomography (CT) combined 3D organ reconstruction bioluminescence imaging was performed to precisely evaluate the metastatic tumor burden on liver of intrasplenic injection mouse model. Human and mouse cancer associated fibroblasts (CAFs) in liver metastasis were separated to culture to study the interaction of LOX and TGF-β1. Patients-derived xenograft (PDX) model was established using liver metastasis of patients to evaluate the therapeutic value of LOX inhibitor β‐aminopropionitrile (BAPN).ResultsCAFs-derived LOX at liver metastatic niche of GC promotes niche formation and outgrowth thus predicts poor prognosis. Meanwhile tumor cells in niche secrete TGF-β1 to nourish CAFs and stimulate them to produce more LOX in turn. The mechanism involved in LOX-mediated proliferation facilitation is enhancement of Warburg effect. The inhibitor of LOX, BPAN could hamper the effect brought by LOX in vivo and in vitro.InterpretationOur study has unveiled a positive feedback loop between CAFs and tumor cells in liver metastasis niche of GC. The core molecule is LOX which facilitates Warburg effect. Targeting LOX with its inhibitor BAPN might serve as a potential therapeutic strategy.FundThis research was supported by the National Natural Science Foundation of China (31872740), the 100-member plan of the Shanghai Municipal Commission of Health and Family Planning (2017BR043), Shanghai Science and Technology Commission Project(17ZR1416800), Renji Hospital Training Fund (PYMDT-003, PYIII-17–015), National Natural Science Foundation of China (81672358), the Shanghai Municipal Education Commission—Gao feng Clinical MedicineGrant Support (20181708), Program of Shanghai Academic/Technology Research Leader(19XD1403400), Science and Technology Commission of Shanghai Municipality (18410721000), Shanghai Municipal Health Bureau (2018BR32), China Postdoctoral Science Foundation (2018M640403), National Natural Science Foundation of China (81701945) and Youth project of Shanghai Municipal Health Commission(20164Y0045).

Lysyl Oxidase Enhances Warburg Effect to Mediate Reciprocal Interactions between Tumor Cells and Cancer Associated Fibroblasts in Liver Metastasis of Gastric Cancer

Background: Liver is one of the most preferred destinations of distant metastasis in gastric cancer (GC). As effective treatment is still limited, the prognosis of GC patients bearing liver metastasis is poor. We filter out lysyl oxidase (LOX) to study its function in the tumor microenvironment (TME) and seek for potential therapeutic targets. Methods: Transcription analysis on 6 cases of liver metastasis of GC patients with respective paired primary tumors and adjacent normal livers was performed. The filtration out of LOX was done using 5 datasets. 69 GC liver metastasis tissues were utilized to perform immunohistochemistry (IHC) and analyze prognosis. Computed Tomography (CT) combined 3D organ reconstruction bioluminescence imaging was performed to precisely evaluate the metastatic tumor burden on liver of intrasplenic injection mouse model. Human and mouse cancer associated fibroblasts (CAFs) in liver metastasis were separated to culture to study the interaction of LOX and TGF-β1. Patients-derived xenograft (PDX) model was established using liver metastasis of patients to evaluate the therapeutic value of LOX inhibitor β‐aminopropionitrile (BAPN). Results: CAFs-derived LOX at liver metastatic niche of GC promotes niche formation and outgrowth thus predicts poor prognosis. Meanwhile tumor cells in niche secrete TGF-β1 to nourish CAFs and stimulate them to produce more LOX in turn. The mechanism involved in LOX-mediated proliferation facilitation is enhancement of Warburg effect. The inhibitor of LOX, BPAN could hamper the effect brought by LOX in vivo and in vitro. Interpretation: Our study has unveiled a positive feedback loop between CAFs and tumor cells in liver metastasis niche of GC. The core molecule is LOX which facilitates Warburg effect. Targeting LOX with its inhibitor BAPN might serve as a potential therapeutic strategy. Funding Statement: This research is supported by the national natural science foundation of China (31872740), The 100-member plan of the Shanghai municipal commission of health and family planning (2017BR043), Shanghai science and technology commission project (17ZR1416800), Renji hospital training fund (PYMDT-003, PYIII-17-015). National Natural Science Foundation of China (81672358, to Z.-G. Zhang), the Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20181708, to Z.-G. Zhang), Program of Shanghai Academic/Technology Research Leader (19XD1403400, to Z.-G. Zhang), Science and Technology Commission of Shanghai Municipality (18410721000, to Z.-G. Zhang) and Shanghai Municipal Health Bureau (2018BR32, to Z.-G. Zhang). National Natural Science Foundation of China, No. 81701945. Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The whole process of specimen collection and experiment performance were approved by the local ethics committee in Renji Hospital, with all patients’ informed consents.

C-terminal of E1A binding protein 1 enhances the migration of gastric epithelial cells and has a clinicopathologic significance in human gastric carcinoma.

BackgroundRecent studies have claimed that the C-terminal of E1A binding proteins (CtBPs) influence tumorigenesis through participating in cell signal transduction in various human tumors. However, the detailed expression profiles of CtBP isoforms in human gastric cancer (GC) and the molecular mechanisms of CtBP involvement in tumor cell phenotypes warrant further investigation.Materials and methodsThe expression of CtBPs in GC cell lines and a human gastric epithelial cell line were explored via RT-qPCR and Western blotting assays. Moreover, the expression profiles of CtBPs in GC and histologically noncancerous tissues were explored by immunohistochemistry. To explore the effects of CtBP1 on the metastatic phenotype in GC, gastric epithelial cells were transfected with a eukaryotic expression plasmid to overexpress CTBP1, and the endogenous CtBP1 or JAK1 in GC cells was silenced through an RNA interference (RNAi) method. These transfections were validated via Western blotting, and the activation state of the JAK1/Stat3 signaling pathway was also explored via Western blotting. Furthermore, the malignant phenotype of GC cells was evaluated via a Cell Counting Kit-8 (CCK8) assay, colony formation assay, transwell assay, and wound-healing experiment.ResultsOur data revealed that the expression of CtBP1, but not CTBP2, was upregulated in 102 GC tissue samples compared with 98 noncancerous tissue samples, and the elevated expression level of CtBP1 was notably associated with distant metastasis. CTBP1 modulated cell migration and invasion through the JAK1/Stat3 signaling pathway in gastric epithelial cells. In addition, genetic silence of CtBP1 expression in GC cells notably constrained cell proliferation, invasion and migration abilities through inhibiting the activation of the JAK1/Stat3 pathway in GC cells.ConclusionOur data reveal that the knockout of CtBP1 notably constrains distant metastasis in GC through the JAK1/Stat3 pathway, suggesting that targeting CtBP1 is a practical anti-tumor approach to restrain tumor progression in GC.

MMP-9 secreted by tumor associated macrophages promoted gastric cancer metastasis through a PI3K/AKT/Snail pathway

PurposeThe distant metastasis in gastric has become an obstacle for treatment in clinic. However, the underlying mechanism is not well illustrated. Here, our aim is to reveal the mechanism and try to explore the potential strategy to overcome the distant metastasis. Materials and methodsIHC was used to detect the expressions of target proteins. H&E staining was used to evaluate the lung metastasis. Using qRT-PCR and ELISA, we detected the expression of target genes and secreted proteins. Western bolt was used to examine the target proteins expression. Wound healing and transwell assay were used to examine the ability of cell to invasion and migration. Using IF, PI3K/AKT/Snail was examined. Animal models were applied to evaluate the killing efficiency in vivo. ResultsHere, we observed accumulated CD68 (a marker of TAMs) in samples from gastric cancer patients with metastasis compared with that in samples from non-metastasis patients. And the expression of CD68 was negatively correlated with patients’ survival time. Then, we found that TAMs enhanced the ability of cancer cells to migration and invasion in vitro and in vivo. Further, we revealed that the distant metastasis was induced by TAMs through secreting MMP-9, which induced epithelial to mesenchymal transition (EMT) process through the transcription factor Snail. Further, applying proenzyme inhibitor of MMP-9 significantly enhanced the killing efficiency of chemotherapeutic drugs and reduced the lung metastasis. ConclusionOur data showed that TAMs facilitate the EMT process via an MMP-9/PI3K/AKT/Snail dependent pathway, while blocking this signaling pathway with MMP-9 proenzyme inhibitor could suppress distant metastasis in gastric cancer.

Application of Overlap anastomosis to Billroth I digestive tract reconstruction after laparoscopic distal gastrectomy in gastric cancer

Objective: To investigate the application value of Overlap anastomosis in Billroth I digestive tract reconstruction after laparoscopic distal gastrectomy in gastric cancer. Methods: Clinical data of 68 stage T1-2 gastric cancer patients undergoing laparoscopic distal gastrectomy for D2 radical gastrectomy from January 2015 to January 2016 at China Japan Union Hospital of Jilin University were retrospectively analyzed. Inclusion criteria: (1) no distant metastasis of gastric cancer confirmed by gastroscopy and pathology before surgery; (2) T1-2 tumor with diameter <3 cm; (3) the lesion locating in the antrum of the stomach with distance >1 cm from the pylorus, and no invasion into middle area; (4) R0 resection confirmed by postoperative pathology; (5) no history of abdominal surgery. Among 68 cases,23 cases were in Overlap anastomosis group and 45 cases in Billroth I anastomosis group. D2 lymph node dissection and distal gastrectomy were performed in both groups. In the Overlap anastomosis group, the duodenum and stomach were severed by a linear stapler under endoscopy, and the residual gastric curve anastomotic opening was selected. According to the tension between the duodenum and the remnant stomach, the anastomotic opening was selected at the upper edge of the remnant duodenum, and the anastomosis between the posterior wall of the remnant stomach and the upper wall of the duodenum was completed by placing the stapler under endoscopy. Then the common opening was closed and the remnant duodenum was resected. In the traditional Billroth I anastomosis group, pneumoperitoneum was discontinued after amputation of the duodenum under laparoscopy. The median incision of the upper abdomen was 9-12 cm. The distal stomach was pulled out to complete the excision of specimens, the extraction of specimens and Billroth I digestive tract reconstruction. The intraoperative and postoperative conditions of the two groups were compared with student t test (continuous variable) and chi-square test (categorica variable). Results: Of the 68 patients,39 were males and 29 were females,with age of (65.5±10.2)(51 to 77)years. Differences in baseline data between Overlap group and Billroth I group were not statistically significant (all P>0.05). Laparoscopic surgery was successfully performed in both groups without conversion to open operation. As compared with the Billroth I group, the Overlap group had significantly shorter operation time [(149.8±10.1) minutes vs. (169.8±15.3) minutes, t=5.658,P=0.008], shorter anastomotic time of digestive tract reconstruction [(31.2±3.8) minutes vs. (36.3±3.3) minutes, t=3.389, P=0.003] and shorter abdominal incision length [(4.5±0.9) cm vs.(11.0±2.3) cm, t=13.244,P=0.004]. There were no significant differences between two groups in intraoperative blood loss [(92.9±22.4) ml vs. (87.0±7.3) ml,t=1.186,P=0.366], number of lymph node dissected (28.4±5.7 vs. 27.3±5.2, t=0.838, P=0.383), postoperative flatus time [(4.4±2.1) days vs.(4.2±1.8) days, t=0.391, P=0.563], morbidity of postoperative complication [4.3%(1/23) vs. 6.7%(3/45), χ2=0.148,P=0.701]. All the patients were followed up for 28±10 (10-46) months. There were no long-term complications, recurrence or death in two groups. Conclusion: Overlap anastomosis in Billroth I digestive tract reconstruction after laparoscopic distal gastrectomy is safe and effective, and can reduce the anastomosis time.

MicroRNA-7 as a potential therapeutic target for aberrant NF-\u03baB-driven distant metastasis of gastric cancer

BackgroundDysregulated miR-7 and aberrant NF-κB activation were reported in various human cancers. However, the expression profile, clinical relevance and dysregulated mechanism of miR-7 and NF-κB RelA/p65 in human gastric cancers (GC) metastasis remain largely unknown. This study is to investigate the expression profile, clinical relevance and dysregulated mechanism of miR-7 and NF-κB RelA/p65 in GC and to explore the potential therapeutic effect of miR-7 to GC distant metastasis.MethodsTCGA STAD and NCBI GEO database were used to investigate the expression profile of miR-7 and NF-κB RelA/p65 and clinical relevance. Lentivirus-mediated gene delivery was applied to explore the therapeutic effect of miR-7 in GC. Real-time PCR, FACS, IHC, IF, reporter gene assay, IP, pre-miRNA-7 processing and binding assays were performed.ResultsLow miR-7 correlated with high RelA/p65 in GC with a clinical relevance that low miR-7 and high RelA/p65 as prognostic indicators of poor survival outcome of GC patients. Moreover, an impaired pre-miR-7 processing caused by dysregulated Dicer1 expression is associated with downregulated miR-7 in GC cells. Functionally, delivery of miR-7 displays therapeutic effects to GC lung and liver metastasis by alleviating hemangiogenesis, lymphangiogenesis as well as inflammation cells infiltration. Mechanistically, miR-7 suppresses NF-κB transcriptional activity and its downstream metastasis-related molecules Vimentin, ICAM-1, VCAM-1, MMP-2, MMP-9 and VEGF by reducing p65 and p-p65-ser536 expression. Pharmacologic prevention of NF-κB activator LPS obviously restored miR-7-suppressed NF-κB transcriptional activation and significantly reverted miR-7-inhibited cell migration and invasion.ConclusionsOur data suggest loss of miR-7 in GC promotes p65-mediated aberrant NF-κB activation, facilitating GC metastasis and ultimately resulting in the worse clinical outcome. Thus, miR-7 may act as novel prognostic biomarker and potential therapeutic target for aberrant NF-κB-driven GC distant metastasis.

Long Non-coding RNA LINC00941 as a Potential Biomarker Promotes the Proliferation and Metastasis of Gastric Cancer.

Gastric cancer (GC) is a considerable global health burden. Accumulating evidence suggests that long non-coding RNAs (lncRNAs) are aberrantly expressed in many cancers and play important roles in GC. However, only a few lncRNAs have been functionally characterized. In this study, we identified that long intergenic non-protein coding RNA 941 (LINC00941) is a potential biomarker for diagnosis and prognosis from the cancer genome atlas (TCGA), and we found that the expression of LINC00941 is associated with tumor depth and distant metastasis in GC. Furthermore, functional enrichment analysis of LINC00941 co-expression network demonstrated that LINC00941 might be an essential regulator of tumor metastasis and cancer cell proliferation. To validate our findings, we utilized the loss-of-function analysis to reveal the biological function of LINC00941 in GC cells. Loss-of-function analysis revealed that silence of LINC00941 inhibits GC cells proliferation, migration, and invasion in vitro and modulates tumor growth in vivo. Our findings confirmed that LINC00941 plays an important oncogenic function in GC and may serve as a potential biomarker for diagnosis and prognosis of GC.

Significance of the Lysyl Oxidase Members Lysyl Oxidase Like 1, 3, and 4 in Gastric Cancer

Background/Aims: Lysyl oxidase (LOX) family members play a key role in modifying the primary tumor microenvironment by crosslinking collagens and elastin in the extracellular matrix. The aim of this study was to analyze the LOX-like (LOXL)1, LOXL3, and LOXL4 expressions in gastric cancer tissue by immunohistochemical staining. Methods: The correlations between the clinicopathological features of 597 primary gastric carcinomas and LOX family members – LOXL1, LOXL3, and LOXL4 – were investigated by immunohistochemical studies. The effect of the transforming growth ­factor β1 (TGFβ1) on the expressions of LOXL1, LOXL3, and LOXL4 in gastric cancer was examined using diffuse-type gastric cancer cell lines in vitro. Results: The expressions of LOXL1, LOXL3, and LOXL4 were correlated with T invasion, lymph node metastasis, and lymphatic and venous invasion. LOXL1 expression was associated with histological intestinal-type and expanding growth patterns. The overall survival of patients with LOXL1-, LOXL3-, or LOXL4-positive cancer was poorer than those with negative cancer. LOXL3 and LOXL4 mRNA expressions were significantly high in diffuse-type gastric cancer cells with high invasion ability. TGFβ decreased the LOXL1 expression and increased LOXL3 and LOXL4 expression. Conclusion: LOXL1, LOXL3, and LOXL4 expressions are associated with distant metastasis of gastric cancer.