Invasion Of Gastric Carcinoma Research Articles

Nucleobindin 2 inhibits senescence in gastric carcinoma

Here, we focused on the role of Nucleobindin 2 (NUCB2), a multifunctional protein, in gastric carcinoma (GC) progression. NUCB2 expression was investigated in 150 GC cases (20 non-invasive (pT1) and 130 invasive (pT2/pT3/pT4) tumors) by immunohistochemistry (IHC), and in situ hybridization for detection of the mRNA in 21 cases. Using GC cell lines, we determined whether NUCB2 expression was associated with specific cellular phenotypes. In GC clinical samples, NUCB2 was transcriptionally upregulated when compared to normal tissues. High NUCB2 expression was associated with clinicopathological factors including deep tumor invasion, lymphovascular invasion, lymph node metastasis, and advanced clinical stages, and was a significant independent predictor of unfavorable progression-free survival in 150 non-invasive and invasive GC patients. Similar findings were also evident in 72 invasive GC cases in which patients received post-operative chemotherapy, but not in 58 invasive tumors from patients who did not receive the chemotherapy. In cell lines, NUCB2 knockout inhibited proliferation, susceptibility to apoptosis, and migration capability by inducting cellular senescence; this was consistent with higher proliferation and apoptotic indices in the NUCB2 IHC-high compared to NUCB2 IHC-low GC cases. NUCB2-dependent inhibition of senescence in GC engenders aggressive tumor behavior by modulating proliferation, apoptosis, and migration.

LINC00460 mediates HMGA2 expression through binding to miRNA-143-5p competitively in gastric carcinoma.

Compelling evidence has manifested a strong association between aberrant expression of long noncoding RNAs (lncRNAs) and gastric carcinoma (GC) development. Nonetheless, biological impacts of differentially expressed lncRNAs (DElncRNAs) on GC are not scrutinized. Bioinformatics methods were employed for differential expression analysis and target gene prediction. MTT, colony formation, and Transwell methods were implemented for GC cell proliferation, migration, and invasion assessment. Western blot was implemented to test the protein level. The binding of genes was tested with dual-luciferase and RNA binding protein immunoprecipitation (RIP) approaches. Noticeably high level of LINC00460 was observed in GC tissues and cells. LINC00460 silencing constrained proliferation, migration, and invasion of GC cells. FISH and nuclear-cytoplasmic separation assays confirmed the main presentation of LINC00460 in the cytoplasm. Bioinformatics predicted that LINC00460 had binding sites to miRNA-143-5p, which was upregulated in GC. Dual luciferase and RIP experiments also confirmed the binding relationship. Concurrent silencing of LINC00460s and miRNA-133-5p rescued the repressive influence of sh-LINC004600 on GC cell proliferation, migration, and invasion. HMGA2 was predicted to be a target gene downstream of miRNA-143-5p, their binding relationship was validated via dual luciferase assays. Silencing HMGA2 constrained GC cell proliferation, invasion, and migration. LINC00460 modulated HMGA2 expression via binding miRNA-143-5p, thereby affecting proliferation, invasion, and migration of GC cells. These findings validated that LINC00460 could regulate HMGA2 via sponging miRNA-143-5p to facilitate GC proliferation, invasion, and migration, which provides a deeper understanding of lncRNAs in the development of GC.

Abstract A008: DNA methyltransferase 3A promotes inflammation-associated gastric cancer growth and presents a therapy target for gastric cancer

Abstract Gastric cancer (GC) remains the third leading cause of cancer-related death worldwide. While inflammation is a well-established driver of gastric tumorigenesis, only a small subset of GC patients responds to immunotherapy. One proposed mechanism of immune escape is silencing tumor-antigen expression, and thereby avoiding immune recognition. DNA methyltransferases (DNMTs) are the enzymes responsible for DNA methylation and hence, for the epigenetic silencing of gene expression of tumor-antigens and other immune-related molecules. Interestingly, they are often overexpressed in solid tumors. Epigenetic drugs inhibiting these DNMTs have shown anti-tumor effects in combination with immune checkpoint inhibitors. Here we are studying the role of DNMTs, specifically DNMT3A, in GC mouse models and the possibility of combining DNMT inhibitors with immunotherapy for the treatment of GC. This project utilises various mouse models of GC. We established a Dnmt3a-overexpressing inflammation-driven GC mouse model (gp130FF, A33Dnmt3a). In a second mouse model, mutant Kras, Pi3kca and Tp53 expression results in highly advanced invasive gastric carcinoma formation (KPT model). We successfully established GC organoids of one of these triple mutant tumors, which can be injected subcutaneously into wild type mice and result in allograft tumor formation. DNMT3A overexpression was detected in human GC specimen and associated with bad overall survival of patients. Gastric adenomas of our gp130FF, A33Dnmt3a mouse model have a 10-fold elevated Dnmt3a expression. Importantly, tumor-specific Dnmt3a overexpression significantly increased gastric tumor burden. We have conducted DNA methylation and gene expression analyses to identify differently methylated and expressed genes between gp130FF and gp130FF, A33Dnmt3a gastric adenoma cells. Treatment with the DNMT inhibitor decitabine reduced tumor growth in the inflammation-driven gp130FF gastric adenoma mouse model. In the KPT model, we have identified DNMT3A as being highly expressed in the invasive front of tumors, their liver metastases as well as in the allograft tumors established by the KPT organoids. In this model of advanced GC, treatment with the DNMT inhibitor decitabine significantly decreased tumor growth and we are currently investigating the efficacy of decitabine in combination with anti-PD-1 and/or anti-CTLA-4 immunotherapy. Taken together, we provide evidence for a driver function of Dnmt3a in gastric tumorigenesis and gastric tumor growth. In addition, our findings encourage further studies to investigate the potential of DNMT inhibitors for the treatment of GC. Citation Format: Anne Huber, Christine Dijkstra, Yuba Bhandari, Hariharan Easwaran, Stephen Baylin, Matthias Ernst, Moritz Eissmann. DNA methyltransferase 3A promotes inflammation-associated gastric cancer growth and presents a therapy target for gastric cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A008.

Nucleobindin-2/nesfatin-1 enhances the cell proliferation, migration, invasion and epithelial-mesenchymal transition in gastric carcinoma.

Nesfatin‐1, a newly discovered adipokine derived from nucleobindin‐2 (NUCB2), has been described as a new prognostic marker in cancers. This study aimed to explore the functional role of NUCB2/nesfatin‐1 in the cell proliferation, migration and invasion in gastric carcinoma (GC). The expressions of NUCB2/nesfatin‐1 in GC tissues and normal adjacent tissues (NATs) were compared, and the effect of inhibition of NUCB2/nesfatin‐1 on the cell proliferation, migration, invasion and epithelial‐mesenchymal transition (EMT) in GC cell line SGC‐7901 was investigated. Cell transfection was conducted to inhibit NUCB2/nesfatin‐1 by short hairpin RNA. Cell proliferation, migration and invasion abilities were determined using cell counting kit‐8 (CCK‐8), 5‐ethynyl‐2′‐deoxyuridine (EdU), wound healing and transwell assays, respectively. The expressions of EMT markers E‐Cadherin and N‐Cadherin were determined using western blotting. The expression of NUCB2/nesfatin‐1 protein in GC tissues was significantly increased compared with that in NATs. Consistently, the serum concentrations of NUCB2/nesfatin‐1 were significantly higher in patients with GC as compared with those in the control group. Moreover, the results of CCK‐8 assay and EdU assay indicated that knockdown of NUCB2/nesfatin‐1 could markedly decrease SGC‐7901 proliferation. Furthermore, the results of wound healing assay and transwell assay demonstrated that knockdown of NUCB2/nesfatin‐1 significantly suppressed SGC‐7901 migration and invasion abilities. Additionally, knockdown of NUCB2/nesfatin‐1 decreased the expressions of N‐Cadherin and increased the expressions of E‐Cadherin in SGC‐7901 cells. These findings suggest that knockdown of NUCB2/nesfatin‐1 suppressed the proliferation, migration, invasion and EMT of SGC‐7901 cells, suggesting a potentially promising therapeutic target for GC.

Integrin \u03b21 orchestrates the abnormal cell-matrix attachment and invasive behaviour of E-cadherin dysfunctional cells

BackgroundTumour progression relies on the ability of cancer cells to penetrate and invade neighbouring tissues. E-cadherin loss is associated with increased cell invasion in gastric carcinoma, and germline mutations of the E-cadherin gene are causative of hereditary diffuse gastric cancer. Although E-cadherin dysfunction impacts cell–cell adhesion, cell dissemination also requires an imbalance of adhesion to the extracellular matrix (ECM).MethodsTo identify ECM components and receptors relevant for adhesion of E-cadherin dysfunctional cells, we implemented a novel ECM microarray platform coupled with molecular interaction networks. The functional role of putative candidates was determined by combining micropattern traction microscopy, protein modulation and in vivo approaches, as well as transcriptomic data of 262 gastric carcinoma samples, retrieved from the cancer genome atlas (TCGA).ResultsHere, we show that E-cadherin mutations induce an abnormal interplay of cells with specific components of the ECM, which encompasses increased traction forces and Integrin β1 activation. Integrin β1 synergizes with E-cadherin dysfunction, promoting cell scattering and invasion. The significance of the E-cadherin-Integrin β1 crosstalk was validated in Drosophila models and found to be consistent with evidence from human gastric carcinomas, where increased tumour grade and poor survival are associated with low E-cadherin and high Integrin β1 levels.ConclusionsIntegrin β1 is a key mediator of invasion in carcinomas with E-cadherin impairment and should be regarded as a biomarker of poor prognosis in gastric cancer.

Induction of Gastric Cancer by Successive Oncogenic Activation in the Corpus

Metaplasia and dysplasia in the corpus are reportedly derived from de-differentiation of chief cells. However, the cellular origin of metaplasia and cancer remained uncertain. Therefore, we investigated whether pepsinogen C (PGC) transcript-expressing cells represent the cellular origin of metaplasia and cancer using a novel Pgc-specific CreERT2 recombinase mouse model. We generated a Pgc-mCherry-IRES-CreERT2 (Pgc-CreERT2) knock-in mouse model. Pgc-CreERT2/+ and Rosa-EYFP mice were crossed to generate Pgc-CreERT2/Rosa-EYFP (Pgc-CreERT2/YFP) mice. Gastric tissues were collected, followed by lineage-tracing experiments and histologic and immunofluorescence staining. We further established Pgc-CreERT2;KrasG12D/+ mice and investigated whether PGC transcript-expressing cells are responsible for the precancerous state in gastric glands. To investigate cancer development from PGC transcript-expressing cells with activated Kras, inactivated Apc, and Trp53 signaling pathways, we crossed Pgc-CreERT2/+ mice with conditional KrasG12D, Apcflox, Trp53flox mice. Expectedly, mCherry mainly labeled chief cells in the Pgc-CreERT2 mice. However, mCherry was also detected throughout the neck cell and isthmal stem/progenitor regions, albeit at lower levels. In the Pgc-CreERT2;KrasG12D/+ mice, PGC transcript-expressing cells with KrasG12D/+ mutation presented pseudopyloric metaplasia. The early induction of proliferation at the isthmus may reflect the ability of isthmal progenitors to react rapidly to Pgc-driven KrasG12D/+ oncogenic mutation. Furthermore, Pgc-CreERT2;KrasG12D/+;Apcflox/flox mice presented intramucosal dysplasia/carcinoma and Pgc-CreERT2;KrasG12D/+;Apcflox/flox;Trp53flox/flox mice presented invasive and metastatic gastric carcinoma. The Pgc-CreERT2 knock-in mouse is an invaluable tool to study the effects of successive oncogenic activation in the mouse corpus. Time-course observations can be made regarding the responses of isthmal and chief cells to oncogenic insults. We can observe stomach-specific tumorigenesis from the beginning to metastatic development.

Minimally Invasive Oncologic Upper Gastrointestinal Surgery can be Performed Safely on all Weekdays: A Nationwide Cohort Study

BackgroundExisting literature suggests deteriorating surgical outcome of esophagogastric surgery as the week progresses. However, these studies were conducted in the pre-centralization and pre-minimally invasive era. In addition, they failed to correct for fixed weekdays of esophagogastric cancer surgery among hospitals. This study aimed to describe the impact of weekday of minimally invasive upper gastrointestinal surgery on short-term surgical outcomes.MethodsAll patients registered in the Dutch Upper Gastrointestinal Cancer Audit who underwent curative minimally invasive esophageal or gastric carcinoma surgery in 2015–2019, were included in this nationwide cohort study. Using multilevel multivariable logistic regression, the impact of weekday of surgery on 14 short-term surgical outcomes was investigated. To correct for interhospital variance in fixed weekday(s) of surgery multilevel analyses was used. Results were adjusted for patient, tumor, and treatment characteristics using multivariable logistic regression analyses.ResultsThis study included 4,102 patients undergoing minimally invasive upper gastrointestinal surgery (2,968 esophageal cancer and 1,134 gastric cancer patients). Weekday of surgery did not impact postoperative complications, severe postoperative complications, surgical/technical complications, medical complications, anastomotic leakage, complicated postoperative course, failure to rescue, surgical radicality, lymph node yield, 30-day/in-hospital mortality, reinterventions, length of ICU stay, 30-day readmission, and textbook outcome after neither esophageal cancer nor gastric cancer surgery.ConclusionsMinimally invasive esophagogastric surgery can be performed safely on all weekdays with respect to short-term surgical outcomes, which is important information for operation room scheduling.

Prognostic role of MUC-2 expression in patients with gastric carcinoma: a systematic review and meta-analysis.

This meta-analysis aimed to assess the association of MUC-2 expression with clinicopathological parameters in gastric carcinoma (GC) patients. Clinical databases based on the study aim were searched in detail. The relative risk ratios (RRs) and associated 95% confidence intervals (95% CIs) were computed after eligible trials were included in the study. Nineteen trials involving 2,363 GC patients were included in this meta-analysis. The expression of MUC-2 showed correlation with clinical stage (I/II vs. III/IV) (RR = 1.09, 95% CI: 1.00-1.18, I2 = 24%, p = 0.194), and lymphatic invasion (present vs. absent) (RR = 0.83, 95% CI: 0.72-0.95, I2 = 22.3%, p = 0.252). However, no significant association was identified between the MUC-2 expression and other clinicopathological parameters, including gender (male vs. female), tumor size (>5 vs. ≤5 cm), Lauren's classification (intestinal vs. diffuse), tumor differentiation (poorly vs. well and moderately), lymph node metastasis (present vs. absent), vascular invasion (present vs. absent), and 5-year survival (yes vs. no) of GC patients. Our meta-analysis findings suggested that MUC-2 positive cases were correlated with lower tumor stage and lower rate of lymphatic invasion. Further clinical studies are warranted to confirm the role of MUC-2 in clinical practice.

Proteasome Subunit Alpha Type 7 Promotes Proliferation and Metastasis of Gastric Cancer Through MAPK Signaling Pathway.

Proteasome subunit alpha type 7 (PSMA7) shows acarcinogenic effect on various human malignancies, but its role and regulatory mechanism in gastric carcinoma (GC) remain unclear. This study aimed to explore the role and mechanism of PSMA7 in GC. In this study, PSMA7 expressions in GC cells and tissues were detected, and relationships between PSMA7 and clinicopathological features were explored. Then, PSMA7 levels in human GC cells were intervened, and changes in cell biological behavior were observed in vitro and vivo. Key proteins and downstream factors of MAPK signaling pathway were detected after PSMA7 intervention. PSMA7 was upregulated in GC tissues and cell lines. PSMA7 overexpression was significantly associated with poor pTNM, cTNM stage, and high HP infection. PSMA7 can promote proliferation, invasion, and metastasis of GC cells in vitro and vivo. Furthermore, PSMA7 expression affected the phosphorylation level of JNK, P38, ERK and the expressions of their downstream factors Ap-1, c-myc, P53. PSMA7 can promote GC proliferation, invasion, and metastasis through MAPK signaling pathway in GC cells.

Abstract PO-014: DNA methyltransferases drive gastric cancer growth and present a therapy target for gastric cancer

Abstract Gastric cancer (GC) remains the third leading cause of cancer related death worldwide. While inflammation is a well-established driver of gastric tumorigenesis, only a small subset of GC patients responds to immunotherapy. The understanding of the tumor microenvironment, which suppresses anti-tumor immune responses, is a field of great interest. One proposed mechanism of immune escape is silencing tumor antigen expression by DNA methylation, and thereby avoiding immune recognition. DNA methyltransferases (DNMTs) are the enzymes responsible for DNA methylation and hence, for the epigenetic silencing of gene expression of tumor antigens and other immune related molecules. DNMTs are often overexpressed in solid tumors. Epigenetic drugs inhibiting these DNMTs have shown anti-tumor effects in combination with immune checkpoint inhibitors by re-activating the expression of tumor antigens, amongst others. Here we are studying the role of DNMTs in GC mouse models and the possibility of combining DNMT inhibitors with immunotherapy for the treatment of GC. This project utilizes various mouse models of GC. The Gp130Y757F/Y757F (gp130FF) mutant mouse model develops spontaneous inflammation driven gastric adenomas. We established a gp130FF Dnmt3a overexpressing gastric cancer mouse model (gp130FF, A33Dnmt3a) where Dnmt3a overexpression occurs in gastric tumors. In a second mouse model, mutant Kras, Pi3kca and Tp53 expression results in highly advanced invasive gastric carcinoma formation (KPT model). We successfully established gastric cancer organoids of one of these triple mutant tumors (KPT organoids) which can be injected subcutaneously into wild type mice and result in allograft tumor formation. DNMT3A overexpression was detected in human GC specimen and associated with bad overall survival of patients. Gastric adenomas of our (gp130FF, A33Dnmt3a mouse model have a 10-fold elevated Dnmt3a expression. Importantly, tumor specific Dnmt3a overexpression significantly increased gastric tumor burden. In the KPT model, we have identified DNMT3A as being highly expressed in the invasive front of tumors, their liver metastases as well as in the allograft tumors established by the KPT organoids. In this model of advanced gastric cancer, treatment with the DNMT inhibitor decitabine significantly decreased tumor growth and we are currently investigating the efficacy of decitabine in combination with anti PD 1 immunotherapy. Taken together, we provide evidence for a driver function of Dnmt3a in gastric tumorigenesis and gastric tumor growth. In addition, we demonstrate the vulnerability of an aggressive gastric carcinoma model to DNMT inhibition and hence its non-oncogene addiction to DNMTs. Therefore, our findings encourage further studies to investigate the potential of DNMT inhibitors for the treatment of GC. Citation Format: Anne Huber, Christine Dijkstra, Matthias Ernst, Moritz Eissmann. DNA methyltransferases drive gastric cancer growth and present a therapy target for gastric cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-014.

Abstract 3834: Histone methyltransferase SET8 is regulated by miR-192/-215 and induces oncogene-induced senescence via p53-dependent DNA damage in human gastric carcinoma cells

Abstract Purpose: This aim of study was to investigate the clinicopathologic significance and potential role of histone methyltransferase SET8 in the progression of gastric carcinoma (GC). Experimental Design: SET8 was screened out by gene microarray in gastric cell lines with or without miR-192/-215 inhibitors or mimics. The effects of SET8 on cell proliferation, invasion, and metastasis were examined using EdU assays, invasion studies, subcutaneous tumor experiments, and tail-vein injection in nude mice. Immunohistochemical staining was performed to detect SET8 expression in GC tissues, and real-time PCR was performed to examine the correlations between miR-192/-215 and SET8. SA-β-Gal staining assays were performed to identify the occurrence of senescence. Senescence-associated proteins were examined by real-time PCR and Western blotting. Results: SET8 regulated by miR-192/-215 displayed decreased expression in GC. Inhibition of miR-192/-215 resulted in weakened proliferation, migration, and invasion in GC. The 3'UTR of SET8 was targeted by miR-192/-215, and SET8 siRNA treatment successfully rescued the biological phenomenon. SET8 was found to trigger oncogene-induced senescence (OIS) in GC in vivo and in vitro, highlighting the functional mechanism of the miR-192/-215/SET8 axis in GC. During OIS, p53 and p21 were key genetic switch points. Taken together, these data show that the miR-192/-215/SET8/p53 circuit is a key regulator of GC promotion and is highly associated with proliferation, migration, and metastasis. Conclusions: Our findings reveal that SET8 functions via the OIS-signaling pathway as a negative regulator of metastasis. This provides an experimental rationale for investigation of the OIS-signaling pathway as a potential therapeutic target in GC. Supported by: National Nature Science Foundation of China (81772592) to Z.J.; National Nature Science Foundation of China (81871969) to X.Z.; National Natural Youth Science Foundation of China (31601028) to Y.P.; Guangdong Provincial Key Laboratory of Regional Immunity and Diseases (2019B030301009) to Z.J. Citation Format: Xiaojing Zhang, Yin Peng, Fan Hu, Yuli Gao, Jin Zhe, Stephenj Meltzer. Histone methyltransferase SET8 is regulated by miR-192/-215 and induces oncogene-induced senescence via p53-dependent DNA damage in human gastric carcinoma cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3834.

XTP8 stimulates migration and invasion of gastric carcinoma through interacting with TGIF1.

To determine expression characteristics of XTP8 and TGIF1 in gastric carcinoma (GC), and the potential roles of XTP8/TGIF1 axis in influencing the progression of GC. The expression levels of XTP8 and TGIF1 in GC tissues and cells were detected. Their functions in prognosis in GC patients were evaluated by the Kaplan-Meier method. The correlation between the XTP8 level and the pathological indexes of the GC patients were analyzed. The changes in the proliferation, migration, and invasion capacities of MKN-45 and SGC-7901 cells affected by XTP8 and TGIF1 were assessed. The interaction between XTP8 and TGIF1 was determined through Dual-Luciferase reporter gene assay and rescue experiments. XTP8 was upregulated in GC tissues and cells. XTP8 level was positively correlated with lymphatic and distant metastasis, as well as poor prognosis of GC patients. The silence of XTP8 attenuated proliferation, migration, and invasion capacities of MKN-45 and SGC-7901 cells. TGIF1 was the downstream gene binding to XTP8, which was downregulated in GC, and XTP8 negatively regulated the TGIF1 level in GC tissues. Importantly, the knockdown of TGIF1 could abolish the regulatory effect of XTP8 on GC cell behaviors. XTP8 is upregulated in GC and is closely linked to lymphatic metastasis, distant metastasis, and poor prognosis of GC patients. Besides, it accelerates the malignant progression via negatively regulating TGIF1.

Dihydroartemisinin inhibits the growth and invasion of gastric cancer cells by regulating cyclin D1-CDK4-Rb signaling

BackgroundDihydroartemisinin (DHA), a semisynthetic derivative of artemisinin, has a broad range of biological properties, including antitumor activity. However, the mechanisms by which DHA affects the tumorigenesis of gastric carcinoma (GC) are poorly understood. Material and methodsThe targets of DHA were identified by network pharmacology, and the association of CDK4 with clinicopathological characteristics and prognosis in patients with GC was analyzed by using TCGA data. CCK8, Transwell and flow cytometric analyses, as well as a tumor xenograft model, were used to assess the effects of DHA on the growth and migration of GC cells. qRT-PCR and Western blot analyses were used to determine the effects of DHA on the cyclin D1-CDK4-Rb signaling pathway. ResultsWe identified 13 DHA targets and measured their expression of whichCDK4 expression levels were substantially higher in GC tissues than those in adjacent normal tissues, and high CDK4 expression acted as an independent prognostic factor of poor survival in patients with GC. DHA suppressed cell proliferation, migration and invasion in vitro and in vivo and induced G1 phase cell cycle arrest in a dose-dependent manner by regulating cyclin D1-CDK4-Rb signaling. ConclusionsDHA inhibits the tumorigenesis and invasion of GC by regulating cyclin D1-CDK4-Rb signaling and may provide therapeutic strategies for the treatment of GC.

The Role of Matrix Metalloproteinase-2 Expression in Gastric Cancer Susceptibility: A Systematic Review

Context: Gastric carcinoma (GC) is the most commonly diagnosed cancer that has been one of the main causes of cancer death worldwide. The matrix metalloproteinase-2 (MMP2) gene was expressed in the gastric cancer tissues compared to the matched normal tissues that are associated with the metastasis of gastric cancer cells. Objectives: This systematic review was performed to investigate the role of MMP-2 in gastric cancer among the different population. Evidence Acquisition: We searched on electronic databases such as PubMed, Scopus, Science Direct and Cochrane Library Database without any language restriction for relevant publications which were published until April 2019. Results: Thirty two original and relevant studies that evaluate the association between gastric cancer and MMP-2 were included. This systematic review indicated that increased MMP-2 expression has been seen in gastric cancer. MMP-2 over-expression may play a crucial role in degrading extracellular matrix as well as stimulate angiogenesis. Conclusions: MMP2 over-expression can play a critical role in tumor metastasis, tumor size, invasion, and lymph node invasion in GC.

Expression of CD133 as a cancer stem cell marker in invasive gastric carcinoma.

SummaryIntroductionGastric cancer is considered to be the fourth most common malignancy worldwide and the second cause of cancer deaths. Regarding the cancer stem cells (CSCs) theory, they are a small group of tumor cells with unrestricted self-renewal and differentiation abilities that help tumor formation. There is an interest in the utility of CD133 as a promising marker to detect the tumor stem cell population for a variety of solid malignancies including gastric cancer. Tumors that express stem cell markers such as CD133 are found to be more aggressive tumors with poor prognosis and high liability for recurrence. This study aimed to evaluate the immunohistochemical expression of CD133 in invasive gastric carcinoma and study the relation between CD133 immunohistochemical expression and different clinicopathological parameters.Material and methods77 cases of gastric carcinoma were collected from the surgical pathology unit at the Gastroenterology Center, Mansoura University, Egypt. CD133 expression in tumor tissue was evaluated by immunohistochemistry.ResultsCD133 expression positively correlated with tumor metastasis and recurrence. Multivariate analysis revealed CD133 positivity to be an independent prognostic factor for tumor recurrence (P = 0.03).ConclusionCD133 is a good marker that can predict tumor recurrence and metastasis in gastric carcinoma. Even though, studies regarding CSCs are still in their initial stages especially those related to CD133 in gastric cancer.

The Role of Preoperative 64 MDCT in the Evaluation of Tumor Stage for Advanced Gastric Carcinoma

To evaluate the accuracy of preoperative 64–detector row computer tomography (MDCT) enhanced scanner in tumor stage prediction for advanced gastric carcinoma, the data of 62 patients with advanced gastric cancer who underwent preoperative 64 MDCT were retrospectively analyzed. Pathological tumor stage was based on international TNM stage of Gastric Carcinoma Association. All MDCT results were compared with surgical and postoperative pathologic results. Results showed that the prediction accuracy of MDCT for T2, T3 and T4 stage evaluation is 42.8% (9/21), 80.7% (21/26) and 60.0% (9/15) respectively. The prediction sensitivity for N2 metastasis is 75%, sensitivity is 92%, and accuracy is 88.7%. It is concluded that preoperative 64 MDCT can provide relatively higher accuracy for detection of T3 and T4 layer invasion of gastric carcinoma, and help to predict the N2 lymph node metastasis for AGC.

Assessment of lymphovascular invasion in gastric carcinoma; do they always indicate lymph node metastasis?

Background: Stomach cancer is one of the leading causes of cancer death. The grading and staging of this cancer plays an important prognostic role. Lymphovascular invasion predicts poor outcome in gastric cancer. Among the others, lymphovascular invasion provides useful information for the clinical management of patients with gastric cancer. Nevertheless, data about lymphovascular invasion in early-stage and in lymph node-positive gastric cancer are lacking. Hence, significance of lymphovascular invasion to metastatic lymph nodes impacting nodal status in gastric cancer has been studied in this study.Materials and methods: This is a retrospective analysis of twenty nine (29) histologically confirmed gastric carcinoma cases received in the department of Pathology at NMCTH dating from October 2014 to September 2016.Results: There was male preponderance to gastric carcinoma with male to female ratio of 2.2:1. The age varied from 31- 84 years. There were 17 cases (59%) of intestinal type and 11 cases (38%) of diffuse type of gastric carcinoma and 1 case (3%) of adeno-neuroendocrine carcinoma. Microscopic evaluation for depth of invasion showed tumor invasion till the subserosal connective tissue layer (69%) suggesting pT3 stage. lymphovascular invasion was identified in 21 cases (72%). There was statistically significant correlation (p value 0.01) between lymphovascular invasion and nodal status (N0) status. Conclusion: Presence of lymphovascular invasion is considered as poor prognostic marker in case of gastric adenocarcinoma. Pathologist have been reporting their presence or absence in each gastrectomy reports related to gastric carcinoma.This study has established a significant relation between presence of lymphovascular invasion and nodal staging of gastric carcinoma.

Involvement of acid-sensing ion channel 1a in gastric carcinoma cell migration and invasion.

Acidic microenvironment, particularly acid-sensing ion channel 1a (ASIC1a), has been reported to promote carcinoma cell proliferation as well as migration. In this study, we explored the effect of ASIC1a on migration and invasion of gastric carcinoma (GC). ASIC1a expression levels were examined in paired GC and adjacent normal tissues from 16 patients by immunohistochemistry. Reverse transcription real-time PCR and immunoblotting were conducted to assess the ASIC1a expression levels in the GC cell line AGS after transfection with ASIC1a small hairpin RNA (shRNA). Wound healing and transwell invasion assays were utilized to detect metastasis and invasion following ASIC1a silencing. Tumor formation was used to detect the role of ASIC1a in tumorigenicity in vivo. It was found that ASIC1a expression level was significantly higher in GC tissues showing postoperative metastasis compared with non-metastasis and non-tumor tissues. Moreover, silencing of ASIC1a with shRNA significantly down-regulated ASIC1a expression and reduced GC cell migration and invasion. A moderately acidic extracellular environment inhibited GC cell viability. Furthermore, ASIC1a shRNA caused inhibition of tumorigenicity in vivo. Our study is the first report of attenuating the malignant phenotype of GC in vitro and in vivo by suppressing ASIC1a, and suggests a novel approach to study the relationship between ASICs and GC cell migration and invasion.

PRL-3 promotes the peritoneal metastasis of gastric cancer through the PI3K/Akt signaling pathway by regulating PTEN

Peritoneal metastasis is the most frequent cause of death in patients with advanced gastric carcinoma (GC). The phosphatase of regenerating liver-3 (PRL-3) is recognized as an oncogene and plays an important role in GC peritoneal metastasis. However, the mechanism of how PRL-3 regulates GC invasion and metastasis is unknown. In the present study, we found that PRL-3 presented with high expression in GC with peritoneal metastasis, but phosphatase and tensin homologue (PTEN) was weakly expressed. The p-PTEN/PTEN ratio was also higher in GC with peritoneal metastasis than that in the normal gastric tissues. We also found the same phenomenon when comparing the gastric mucosa cell line with the GC cell lines. After constructing a wild-type and a mutant-type plasmid without enzyme activity and transfecting them into GC SGC7901 cells, we showed that only PRL-3 had enzyme activity to downregulate PTEN and cause PTEN phosphorylation. The results also showed that PRL-3 increased the expression levels of MMP-2/MMP-9 and promoted the migration and invasion of the SGC7901 cells. Knockdown of PRL-3 decreased the expression levels of MMP-2/MMP-9 significantly, which further inhibited the migration and invasion of the GC cells. PRL-3 also increased the expression ratio of p-Akt/Akt, which indicated that PRL-3 may mediate the PI3K/Akt pathway to promote GC metastasis. When we transfected the PTEN siRNA plasmid into the PRL-3 stable low expression GC cells, the expression of p-Akt, MMP-2 and MMP-9 was reversed. In conclusion, our results provide a bridge between PRL-3 and PTEN; PRL-3 decreased the expression of PTEN as well as increased the level of PTEN phosphorylation and inactivated it, consequently activating the PI3K/Akt signaling pathway, and upregulating MMP-2/MMP-9 expression to promote GC cell peritoneal metastasis.

Mixed Carcinoma as an Independent Prognostic Factor in Submucosal Invasive Gastric Carcinoma

Mixed carcinoma shows a mixture of glandular and signet ring/poorly cohesive cellular histological components and the prognostic significance of each component is not fully understood. This study aimed to investigate the significance of the poorly cohesive cellular histological component as a risk factor for lymph node metastasis and to examine the diagnostic reliability of endoscopic biopsy. Clinicopathologic characteristics of 202 patients who underwent submucosal invasive gastric carcinoma resection with lymph node dissection in 2005–2012 were reviewed. Mixed carcinoma accounted for 27.2% (56/202) of cases. The overall prevalence of lymph node metastasis was 17.3% (35/202). Lymphatic invasion (P < 0.001), family history of carcinoma (P = 0.025), tumor size (P = 0.004), Lauren classification (P = 0.042), and presence of any poorly cohesive cellular histological component (P = 0.021) positively correlated with the lymph node metastasis rate on univariate analysis. Multivariate analyses revealed lymphatic invasion, family history of any carcinoma, and the presence of any poorly cohesive cellular histological component to be significant and independent factors related to lymph node metastasis. Review of preoperative biopsy slides showed that preoperative biopsy demonstrated a sensitivity of 63.6% and a specificity of 100% in detecting the presence of the poorly cohesive cellular histological component, compared with gastrectomy specimens. The presence of any poorly cohesive cellular histological component was an independent risk factor associated with lymph node metastasis in submucosal invasive gastric carcinoma. Endoscopic biopsy had limited value in predicting the presence and proportion of the poorly cohesive cellular histologic component due to the heterogeneity of mixed carcinoma.