Thiostrepton confers protection against reactive oxygen species-related apoptosis by restraining FOXM1-triggerred development of gastric cancer.

Gastric cancer is a leading cause of tumor-associated death worldwide. Metastasis and chemoresistance are crucial barriers for gastric cancer treatment. The Forkhead Box M1 (FOXM1) transcription factor has been reported as a promising treatment target for various types of tumors, but its effects on gastric cancer progression are not fully understood. In the present study, we found that FOXM1 expression levels were significantly up-regulated in human gastric cancer cell lines and tissues, and its expression was much higher in patients with metastasis. We then found that suppressing FOXM1 with its inhibitor thiostrepton (THIO) significantly reduced the proliferation of gastric cancer cells, while induced G0/G1 and apoptosis. Moreover, reactive oxygen species (ROS) production, mitochondrial impair and autophagy were remarkably provoked in gastric cancer cells treated with THIO, which were required for the regulation of apoptotic cell death. Furthermore, THIO exposure considerably suppressed the migration, invasion and angiogenesis in gastric cancer cells. The inhibitory effects of THIO on tumor growth and metastasis were confirmed in an established gastric cancer xenograft mouse model without detectable toxicity. Intriguingly, our in vitro studies showed that the anti-cancer effects of THIO on gastric cancer were almost abolished upon FOXM1 over-expression, indicating the necessity of FOXM1 suppression in THIO-inhibited tumor growth. In addition, higher FOXM1 expression was detected in gastric cancer cells with chemoresistance. Both in vitro and in vivo studies illustrated that THIO strongly promoted the drug-resistant gastric cancer cells to chemotherapies, proved by the considerably decreased cell proliferation and epithelial-mesenchymal transition (EMT) process. Together, these findings revealed that FOXM1 was a promising therapeutic target for gastric cancer treatment, and THIO exerted potential as an therapeutic agent for the disease.

Role of annexin A family in tumorigenesis and chemoresistance of gastric cancer.

Gastric cancer (GC) is one of the most common cancer types and the fourth leading cause of cancer-related mortality among all malignant tumors worldwide. Due to insidious onset and lack of reliable early diagnostic markers, most GC patients are at an advanced stage at the time of diagnosis. Annexin is an evolutionally-conserved Ca2+-dependent phospholipid-binding protein superfamily, including five members (A, B, C, D, and E). Annexins in the cells of vertebrates comprised the annexin A family, consisting of 12 members in humans. The biological functions of annexin A are Ca2+-signal transduction, vesicle transport, cell proliferation, cell division, cell apoptosis, signal transduction, anti-inflammatory, proangiogenesis, and anticoagulation, most of which overlap with the basic characteristics of tumors. Accumulating evidence indicated that members of the annexin A family are correlated with tumorigenesis and chemoresistance and can be used as potential tumor prognostic factors and targets for biological therapy. Thus, the current review focused on the role and relative mechanisms of the annexin A family in GC.

Circular RNA Circ-0002570 Accelerates Cancer Progression by Regulating VCAN via MiR-587 in Gastric Cancer.

BACKGROUND: Circular RNAs (circRNAs) are closely associated with the occurrences and progress of gastric cancer (GC). We aimed to delve into the function and pathological mechanism of Circular RNA-0002570 (circ-0002570) in GC progression. METHODS: CircRNAs differentially expressed in GC were screened using bioinformatics technology. The expression of circ-0002570 was detected in GC specimens and cells via qRT-PCR, and the prognostic values of circ-0002570 were determined. The functional roles of circ-0002570 on proliferation, migration, and invasion in GC cells were explored in vitro and in vivo. Interaction of circ-0002570, miR-587, and VCAN was confirmed by dual-luciferase reporter assays, Western blotting, and rescue experiments. RESULTS: Circ-0002570 expression was distinctly increased in GC tissues compared to adjacent normal specimens, and GC patients with higher circ-0002570 expressions displayed a short survival. Functionally, knockdown of circ-0002570 resulted in the inhibition of cell proliferation, migration, and invasion, and suppressed tumor growth in vivo. Mechanistically, miR-587 was sponged by circ-0002570. VCAN expression in NSCLC was directly inhibited by miR-587. Overexpression of circ-0002570 prevented VCAN from miR-587-mediated degradation and thus facilitated GC progression. CONCLUSION: The circ-0002570-miR-587-VCAN regulatory pathway promoted the progression of GC. Our findings provided potential new targets for the diagnosis and therapy of GC.

Knockdown of Microtubule Associated Serine/threonine Kinase Like Expression Inhibits Gastric Cancer Cell Growth and Induces Apoptosis by Activation of ERK1/2 and Inactivation of NF-κB Signaling.

Microtubule-associated serine/threonine kinase (MASTL) functions to regulate chromosome condensation and mitotic progression. Therefore, aberrant MASTL expression is commonly implicated in various human cancers. This study analyzed MASTL expression in gastric cancer vs. adjacent normal tissue for elucidating the association with clinicopathological data from patients. This work was then extended to investigate the effects of MASTL knockdown on tumor cells in vitro. The level of MASTL expression in gastric cancer tissue was assessed from the UALCAN, GEPIA, and Oncomine online databases. Lentivirus carrying MASTL or negative control shRNA was infected into gastric cancer cells. RT-qPCR, Western blotting, cell viability, cell counting, flow cytometric apoptosis and cell cycle, and colony formation assays were performed. MASTL was upregulated in gastric cancer tissue compared to the adjacent normal tissue, and the MASTL expression was associated with advanced tumor stage, Helicobacter pylori infection and histological subtypes. On the other hand, knockdown of MASTL expression significantly reduced tumor cell viability and proliferation, and arrested cell cycle at G2/M stage but promoted tumor cells to undergo apoptosis. At protein level, knockdown of MASTL expression enhanced levels of cleaved PARP1, cleaved caspase-3, Bax and p-ERK1/2 expression, but downregulated expression levels of BCL-2 and p-NF-κB-p65 protein in AGS and MGC-803 cells. MASTL overexpression in gastric cancer tissue may be associated with gastric cancer development and progression, whereas knockdown of MASTL expression reduces tumor cell proliferation and induces apoptosis. Further study will evaluate MASTL as a potential target of gastric cancer therapeutic strategy.

Construction of a novel ceRNA network and identification of lncRNA ADAMTS9-AS2 and PVT1 as hub regulators of miRNA and coding gene expression in gastric cancer.

BACKGROUND: Studies on the interactions of single long non-coding RNA, microRNA, and mRNA have many limitations; therefore, it is necessary to study the complex regulatory network of gastric cancer (GC) pathogenesis systematically. METHODS: In this study, gene and miRNA expression data for GC were downloaded from The Cancer Genome Atlas and used for transcriptome profiling, differential gene analysis, and construction of an lncRNA-miRNA-mRNA regulatory network in conjunction with an online database to identify the key genes and subnetworks in GC pathogenesis. Real-time quantitative polymerase chain reaction was used to detect the expression of hub lncRNAs in 54 paired GC and matched normal mucosal tissues. RESULTS: We constructed an lncRNA-miRNA-mRNA competitive endogenous RNA regulatory network containing 1,626 network nodes and 2,704 interactions. LncRNA ADAMTS9-AS2 and PVT1 were identified as key node genes in this competitive endogenous RNA network. Quantitative reverse transcription-polymerase chain reaction revealed ADAMTS9-AS2 downregulation and PVT1 upregulation in 54 pairs of GC and normal tissues adjacent to the cancer tissues. CONCLUSIONS: This study systematically analysed the lncRNA-miRNA-mRNA regulatory network in GC and identified ADAMTS9-AS2 and PVT1 as key regulatory genes in this network, providing new understanding of GC pathogenesis and insights for its early diagnosis and treatment.

Acute esophageal obstruction caused by reverse migration of gastric bezoars: A case report.

BACKGROUND: Bezoars can be found anywhere in the gastrointestinal tract. Esophageal bezoars are rare. Esophageal bezoars are classified as either primary or secondary. It is rarely reported that secondary esophageal bezoars caused by reverse migration from the stomach lead to acute esophageal obstruction. Guidelines recommend urgent upper endoscopy (within 24 h) for these impactions without complete esophageal obstruction and emergency endoscopy (within 6 h) for those with complete esophageal obstruction. Gastroscopy is regarded as the mainstay for the diagnosis and treatment of esophageal bezoars. CASE SUMMARY: A 59-year-old man was hospitalized due to nausea, vomiting and diarrhea for 2 d and sudden retrosternal pain and dysphagia for 10 h. He had a history of type 2 diabetes mellitus for 9 years. Computed tomography revealed dilated lower esophagus, thickening of the esophageal wall, a mass-like lesion with a flocculent high-density shadow and gas bubbles in the esophageal lumen. On gastroscopy, immovable brown bezoars were found in the lower esophagus, which led to esophageal obstruction. Endoscopic fragmentation was successful, and there were no complications. The symptoms of retrosternal pain and dysphagia disappeared after treatment. Mucosal superficial ulcers were observed in the lower esophagus. Multiple biopsy specimens from the lower esophagus revealed nonspecific findings. The patient remained asymptomatic, and follow-up gastroscopy 1 wk after endoscopic fragmentation showed no evidence of bezoars in the esophagus or the stomach. CONCLUSION: Acute esophageal obstruction caused by bezoars reversed migration from the stomach is rare. Endoscopic fragmentation is safe, effective and minimally invasive and should be considered as the first-line therapeutic modality.

Circular RNA is a popular molecule in tumors of the digestive system (Review).

Most tumors of the digestive system, including esophageal, gastric, liver and colorectal cancer, are malignant tumors that are associated with rates of high morbidity and mortality. The lack of effective methods for early diagnosis is an important cause of poor prognosis for these malignancies. Circular RNAs (circRNAs) belong to a family of endogenous, covalently closed non­coding RNAs that are characterized as having no 5' cap structures or 3' poly­A tails. Shortly following discovery, circRNAs were considered to be a product of mis­splicing and have no significant biological function. However, in recent years, accumulating evidence is demonstrating that they serve key roles in tumorigenesis and have the potential to serve as diagnostic markers. The present article summarizes the biogenesis and function of circRNAs and reviews their role in seven common types of tumor of the digestive system whilst exploring their potential as tumor markers and the significant roles they can serve in the digestive system, in addition to providing a referencing point for future studies of digestive system malignancies.

The Roles of microRNAs in Multidrug-Resistance Mechanisms in Gastric Cancer.

Multidrug resistance (MDR) is one of the most significant reasons for the chemotherapeutics failure in gastric cancer. Although accumulating investigations and researches have been made to elucidate the mechanisms of multidrug resistance, the detail is far from completely understood. The importance of microRNAs in cancer chemotherapeutic resistance has been demonstrated recently, which provides a new strategy to overcome multidrug resistance. The different mechanisms are related to the phenomena of MDR itself and the roles of miRNAs in these multi-mechanisms by which MDR is acquired. In turn, the aim of this review was to summarize recent publications of microRNAs in regulating MDR in gastric cancer, thereby potentially developing as targeted therapies. Further unraveling the roles of microRNAs in MDR mechanisms including the ATP-binding cassette (ABC) transporter family, autophagy induction, cancer stem cell regulation, hypoxia induction, DNA damage and repair, epigenetic regulation, and exosomes in gastric cancer will be helpful for us to win the battle against it.

Nomograms combined with SERPINE1-related module genes predict overall and recurrence-free survival after curative resection of gastric cancer: a study based on TCGA and GEO data.

BACKGROUND: Serpin peptidase inhibitor, clade E, member 1 (SERPINE1) has been investigated as an oncogene and potential biomarker in several cancers, including gastric cancer (GC). This study aimed to investigate SERPINE1 expression and its diagnostic and prognostic value by analyzing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. METHODS: A meta-analysis was performed to investigate SERPINE1 expression levels in GC tissues and adjacent normal tissues. Gene set enrichment, multi experiment matrix (MEM), and protein-protein interaction (PPI) network analyses were performed to identify the most enriched signaling pathways and SERPINE1-related module genes. A Cox regression model was used to develop a nomogram that was able to predict the overall survival (OS) and recurrence-free survival (RFS) of individual patients. RESULTS: Meta-analyses revealed an elevated trend in SERPINE1 expression levels in TCGA [standard mean difference (SMD) =0.95; 95% confidence interval (CI), 0.53-1.36; P<0.001]. The diagnostic meta-analysis results indicated that the area under the curve (AUC) of the summary receiver operating characteristic (SROC) was 0.80 (95% CI, 0.77-0.84). The factors identified to predict OS were age ≥60 years [hazard ratio (HR), 2.14; 95% CI, 1.45-3.16; P<0.01], R2 margins (HR, 2.70; 95% CI, 1.41-5.14; P<0.05), lymph node-positive proportion (HR, 3.38; 95% CI, 2.03-5.63; P<0.001), patient tumor status (HR, 3.33; 95% CI, 2.28-4.87; P<0.001), and OS risk score (HR, 2.72; 95% CI, 1.82-4.05; P<0.05). The following variables were associated with RFS: male sex (HR, 2.55; 95% CI, 1.46-4.45; P<0.01), R2 margins (HR, 13.08; 95% CI, 4.26-40.15; P<0.001), lymph node-positive proportion (HR, 2.55; 95% CI, 1.20-5.45; P<0.05), and RFS risk score (HR, 2.70; 95% CI, 1.82-4.06; P<0.001). The discriminative ability of the final model for OS and RFS was assessed using C statistics (0.755 for OS and 0.745 for RFS). CONCLUSIONS: SERPINE1 was upregulated in GC, showed a high diagnostic value, and was associated with poorer OS and RFS. The OS and RFS risk for an individual patient could be estimated using these nomograms, which could lead to individualized therapeutic choices.

COL4A family: potential prognostic biomarkers and therapeutic targets for gastric cancer.

BACKGROUND: The type IV collagen alpha chain (COL4A) family is a major component of the basement membrane (BM) that has recently been found to be involved in tumor angiogenesis and progression. However, the expression levels and the exact roles of distinct COL4A family members in gastric cancer (GC) have not been completely understood. METHODS: Here, the expression levels of COL4As in GC and normal gastric tissues were calculated by using TCGA datasets and the predicted prognostic values by the GEPIA tool. Furthermore, the cBioPortal and Metascape tools were integrated to analyze the genetic alterations, correlations and potential functions of COL4As, and their frequently altered neighboring genes in GC. RESULTS: Notably, the expression levels of COL4A1/2/4 in GC were higher to those in normal gastric tissues, while the expression levels of COL4A3/5/6 were lower in GC than normal. Survival analysis revealed that lower expression levels of COL4A1/5 led to higher overall survival (OS) rate. Multivariate analysis using the Cox proportional-hazards model indicated that age, gender, pathological grade, metastasis and COL4A5 expression, are independent prognostic factors for OS. However, TNM stage, lymph node metastasis, Lauren's classification, COL4A1-4 and COL4A6 were associated with poor OS but not independent prognostic factors. Function-enriched analysis of COL4As and their frequently altered neighboring genes was involved in tumor proliferation and metastasis in GC. CONCLUSIONS: These results implied that COL4A1/2 were potential therapeutic targets for GC. COL4A3/4/6 might have an impact on gastric carcinogenesis and subsequent progression, whereas COL4A5 was an independent prognostic marker for GC.

Serum miR-551b-3p is a potential diagnostic biomarker for gastric cancer.

BACKGROUND/AIMS: Gastric cancer (GC) is one of the most common gastrointestinal malignancies. Many studies have demonstrated that serum microRNAs have potential applications as non-invasive biomarkers for cancer diagnosis. The aim of the present study was to investigate the expression of serum miR-551b-3p in patients with GC and to explore its potential as a diagnostic biomarker in GC. MATERIALS AND METHODS: The expression of miR-551b-3p was detected using quantitative reverse transcription polymerase chain reaction in preoperative serum samples of 50 patients with GC and 53 healthy individuals. An analysis was performed to determine the correlation between serum miR-551b-3p levels and clinicopathological characteristics of patients with GC. The receiver operating characteristic curve was generated, and the cut-off point of serum miR-551b-3p for the diagnosis of GC was selected. The clinical value of serum miR-551b-3p for GC was analyzed by a consistency test. RESULTS: The expression of serum miR-551b-3p was significantly lower in patients with GC than in healthy individuals (p=0.000). Low level was positively associated with tumor size (p=0.014), depth of invasion (p=0.001), and Tumor-Node-Metastasis stage (p=0.022). The area under the curve for serum miR-551b-3p distinguishing patients with GC from healthy individuals was 0.860 (95% CI: 0.787-0.933, p=0.000), with a specificity of 96.2% and a sensitivity of 70%. The kappa consistency test had a kappa value of 0.667 (p=0.000) in GC. CONCLUSION: Serum miR-551b-3p may potentially serve as a diagnostic biomarker for GC.

Clinical significance of upregulation of mir-196a-5p in gastric cancer and enriched KEGG pathway analysis of target genes.

BACKGROUND: miRNAs are relatively recently discovered cancer biomarkers which have important implications for cancer early diagnosis, treatment and estimation of prognosis. Here we focussed on expression of mir-196a-5p in gastric cancer tissues and cell lines so as to analyse its significance for clinicopathologic characteristics and generate enriched KEGG pathways clustered by target genes for exploring its potential roles as a biomarker in gastric cancer. MATERIALS AND METHODS: The expression of mir-196a-5p in poorly, moderate and well differentiated gastric cancer cell lines compared with GES-1 was detected by RT-qPCR, and the expression of mir-196a-5p in gastric cancer tissues comparing with adjacent non cancer tissues of 58 cases were also assessed by RT- qPCR. Subsequently, an analysis of clinical significance of mir-196a-5p in gastric cancer and enriched KEGG pathways was executed based on the miRWalk prediction database combined with bioinformatics tools DAVID 6.7 and Mirfocus 3.0. RESULTS: RT-qPCR showed that mir-196a-5p was up-regulated in 6 poorly and moderate differentiated gastric cancer cell lines SGC-7901, MKN-45, MKN-28, MGC-803, BGC-823, HGC-27 compared with GES-1, but down-regulated in the highly differentiated gastric cancer cell line AGS. Clinical data indicated mir-196a-5p to beup-regulated in gastric cancer tissues (47/58). Overexpression of mir-196a-5p was associated with more extensive degree of lymph node metastasis and clinical stage (P <0.05; x2 test). Enriched KEGG pathway analyses of predicted and validated targets in miRWalk combined with DAVID 6.7 and Mirfocus 3.0 showed that the targeted genes regulated by mir-196a-5p were involved in malignancy associated biology. CONCLUSIONS: Overexpression of mir-196a-5p is associated with lymph node metastasis and clinical stage, and enriched KEGG pathway analyses showed that targeted genes regulated by mir-196a-5p may contribute to tumorgenesis, suggesting roles as an oncogenic miRNA biomarker in gastric cancer.

Stem cells in gastric cancer.

Gastric cancer (GC) is one of the leading causes of cancer-related mortality worldwide. Cancer stem cells (CSCs), which were first identified in acute myeloid leukemia and subsequently in a large array of solid tumors, play important roles in cancer initiation, dissemination and recurrence. CSCs are often transformed tissue-specific stem cells or de-differentiated transit amplifying progenitor cells. Several populations of multipotent gastric stem cells (GSCs) that reside in the stomach have been determined to regulate physiological tissue renewal and injury repair. These populations include the Villin+ and Lgr5+ GSCs in the antrum, the Troy+ chief cells in the corpus, and the Sox2+ GSCs that are found in both the antrum and the corpus. The disruption of tumor suppressors in Villin+ or Lgr5+ GSCs leads to GC in mouse models. In addition to residing GSCs, bone marrow-derived cells can initiate GC in a mouse model of chronic Helicobacter infection. Furthermore, expression of the cell surface markers CD133 or CD44 defines gastric CSCs in mouse models and in human primary GC tissues and cell lines. Targeted elimination of CSCs effectively reduces tumor size and grade in mouse models. In summary, the recent identification of normal GSCs and gastric CSCs has greatly improved our understanding of the molecular and cellular etiology of GC and will aid in the development of effective therapies to treat patients.

Celecoxib regulates apoptosis and autophagy via the PI3K/Akt signaling pathway in SGC-7901 gastric cancer cells.

Gastric cancer, one of the most common malignancies worldwide, typically has a poor prognosis and poor survival rate. Previous studies have investigated the chemopreventive effect of celecoxib. In the present study, the SGC-7901 human gastric cancer cell line was utilized to examine the chemopreventive mechanisms of celecoxib. The inhibition of cell proliferation was determined using MTT assay, cell apoptosis was monitored by terminal deoxynucleotidyl transferase-mediated dUTP nick end­labeling (TUNEL) and flow cytometry, and cell ultrastructural changes were assessed via transmission electron microscopy. The mRNA expression of Akt, caspase-8 and -9 was examined using quantitative reverse-transcription-polymerase chain reaction (qRT-PCR) and p-Akt, procaspase-8 and -9 were analyzed via western blotting. The results showed that celecoxib inhibited the proliferation of SGC-7901 cells in a time- and dose-dependent manner. Additionally, celecoxib induced apoptosis as substantiated by typical apoptotic bodies, autophagosomes and an increased apoptotic rate. It was found that following celecoxib treatment, Akt mRNA expression was not significantly altered, and that p-Akt protein levels decreased in a time- and dose­dependent manner. Additionally, caspase-8 and -9 mRNA expression was significantly increased, while procaspase-8 and -9 protein expression decreased relative to the time- and dose-dependent effects. These results demonstrated that celecoxib induced apoptosis and autophagy of gastric cancer cells in vitro through the PI3K/Akt signaling pathway. Moreover, our findings suggested that celecoxib induces apoptosis in gastric cancer cells through the mitochondrial and death receptor pathways, providing additional understanding regarding the chemopreventive behaviors of celecoxib and its uses in cancer therapy.

Interaction between cyclooxygenase-2, Snail, and E-cadherin in gastric cancer cells.

AIM: To investigate the mechanisms of how cyclooxygenase-2 (COX-2) regulates E-cadherin in gastric cancer cells. METHODS: COX-2 expression in human gastric cancer cell lines SGC-7901, BGC-823, MGC-803 and AGS were measured at the mRNA and protein level. COX-2 rich cell line SGC-7901 was chosen for subsequent experiments. siRNA mediated gene knockdown was used to investigate the impact of COX-2 on nuclear factor-κB (NF-κB), Snail, and E-cadherin in gastric cancer cells. Gene expression was determined by Western blot and real-time polymerase chain reaction. To analyze whether NF-κB inhibition could interrupt the modulatory effect of COX-2 or prostaglandin E2 (PGE2) on E-cadherin, gastric cancer cells were treated with celecoxib or PGE2, in the presence of NF-κB specific siRNA. RESULTS: Highest expression level of COX-2 was found in SGC-7901 cells, both at mRNA and protein levels. siRNA mediated down-regulation of COX-2 led to a reduced expression of NF-κB and Snail, but an increased expression of E-cadherin in SGC-7901 cells. siRNA mediated down-regulation of NF-κB also led to a reduced expression of E-cadherin and Snail in SGC-7901 cells. However, COX-2 expression did not alter after cells were treated with NF-κB specific siRNA in SGC-7901 cells. Treatment of SGC-7901 cells with celecoxib led to a reduced expression of Snail but an increased expression of E-cadherin. In contrast, treatment of SGC-7901 cells with PGE2 led to an increased Snail and a decreased E-cadherin. However, siRNA-mediated knockdown of NF-κB partially abolished the effect of celecoxib and PGE2 on the regulation of E-cadherin and Snail in SGC-7901 cells. CONCLUSION: COX-2 likely functions upstream of NF-κB and regulates the expression of E-cadherin via NF-κB/Snail signaling pathway in gastric cancer cells.

[Expression and significance of RhoA and NF-ΚB in human gastric carcinoma].

OBJECTIVE: To investigate the expression of RhoA and NF-κB in gastric carcinoma and their correlation with clinicopathological fearures. To determine the effective prognostic factors of long-term suivival of gastric carcinoma patients. METHODS: The role of RhoA and NF-κB in gastric carcinoma was assessed by tissue array technology and the levels of RhoA and NF-κB expression in paraffin-embedded tissues was quantified by immunohistochemistry from 189 cases of gastric carcinoma, 54 cases of their adjacent tissues, and 32 cases of normal gastric mucosa. The prognosis of gastric carcinoma was evaluated by Kaplan-Meier survival analysis and Cox multivariate regression analysis. RESULTS: The positive rates of RhoA expression were 84.7%, 68.5% and 65.6% in gastric carcinoma, adjacent tissues and normal mucosa, respectively. The expression of RhoA in gasric carcinoma was significantly higher than that in adjacent tissues and normal mucosa (P < 0.05). The positive rates of NF-κB expression were 75.1%, 42.6% and 15.6%% in gastric carcinoma, adjacent tissues and normal mucosa, respectively. The expression of NF-κB in gasric carcinoma was significantly higher than that in adjacent tissues and normal mucosa (P < 0.05). RhoA was positively linked with NF-κB (r = 0.203, P = 0.005). In gastric carcinoma, the expression of RhoA was related with depth of invasion (P < 0.05), and the expression of NF-κB was related with depth of invasion and lymph node metastasis (P < 0.05). The Kaplan-Meier survival analysis showed that the tumor size, lymph node metastasis, depth of invasion, expression of RhoA and NF-κB can shorten the cumulative survival rate. With these paramaters entering the Cox multivariate regression analysis mode, it was revealed that expression of NF-κB, lymph node metastasis and depth of invasion are independent prognostic factors. CONCLUSIONS: The overexpression of RhoA and NF-κB is involved in the occurrence and development of gastric carcinoma. RhoA is positively linked with NF-κB. They are correlated with the invasion and metastasis of gastric carcinoma. The expression of NF-κB, lymph node metastasis, depth of invasion are independent prognostic factors playing an important role in prediction of the clinical outcome after radical resection of gastric carcinoma.

Correlations of P21-activated kinase 1 expression to clinicopathological features of gastric carcinoma and patients' prognosis.

BACKGROUND AND OBJECTIVE: Recent studies proved that P21-activated kinase 1 (PAK1) is highly expressed in many kinds of tumor and plays an important role in genesis, development, and metastasis of tumor. We aimed to detect the expression of PAK1 in gastric carcinoma and to analyze its relationship with clinicopathological features and prognosis of gastric carcinoma. METHODS: Tissue microarray and immunohistochemical staining were performed to detect PAK1 in paraffin specimens of 189 gastric carcinomas, 54 paracancer tissues, 40 lymph nodes and 30 healthy tissues. Clinicopathologic features and follow-up data of the patients were analyzed by the Chi2 test and the Kaplan-Meier method. RESULTS: Positive rate of PAK1 was 73.0% in gastric carcinoma, 57.4% in paracancer tissues and 23.3% in healthy controls (Chi2 = 29.364, P < 0.05). Expression of PAK1 was significantly correlated with tumor size, tumor differentiation, lymph node metastasis, Lauren classification and invasive depth (all P < 0.05). The positive rate of PAK1 was significantly higher in primary gastric carcinomas than in metastatic lymph nodes (75.0% vs. 52.5%, Chi2 = 4.381, P < 0.05). Survival analysis using the Kaplan-Meier method showed that the expression of PAK1 was a predictor for poor prognosis of the patients with gastric carcinoma (Chi2 = 6.857, P < 0.01). CONCLUSIONS: Expression of PAK1 is an early molecular event in the tumorigenesis of gastric carcinoma. It is also closely correlated the development of gastric carcinoma and the patients' prognosis.

[Relationship between Ets-1 expression and angiogenesis, clinicopathological features and survival of patients with gastric carcinoma].

OBJECTIVE: To investigate the expression of Ets-1 in gastric carcinoma, para-cancerous tissue and metastatic lymph nodes, and to determine the relationship between Ets-1 expression and clinicopathological features, angiogenesis and survival of patients with gastric carcinoma. METHODS: Gastric carcinoma tissue microarray was used to determine Ets-1 protein expression by SP immunohistochemical staining in 189 advanced gastric cancer, 54 papacancerous tissues, 41 metastatic lymph nodes and 32 control tissues. RESULTS: The positive rates for Ets-1 expression of the carcinoma, paracancerous and control tissues were 71.4%, 29.6% and 18.8%, respectively, with a significant difference among the three groups (P < 0.01). In the cancer tissues, the positive rate of Ets-1 protein expression was significantly associated with depth of invasion and lymph node metastasis (P < 0.01), but not associated with degree of differentiation, Lauren's histological type, sex, age, and size of tumor (P > 0.05). The positive rates for Ets-1 expression of the 41 gastric cancer and 41 metastatic lymph nodes were significantly different (P < 0.05). In metastatic lymph nodes, the positive rate for Ets-1 expression was higher. The MVD in Ets-1 positive tumors was higher than that in the Ets-1 negative tumors, with a significant difference (P < 0.05). Kaplan-Meier survival analysis showed that the survival time of Ets-1-negative patients was longer than that of Ets-1-positive patients (P < 0.05). Cox regression analysis showed that Ets-1 expression was not an independent prognostic factor of gastric carcinoma. CONCLUSION: A higher expression of Ets-1 is involved in carcinogenesis, development, invasion, and metastasis of gastric cancer. Ets-1 plays an important role in angiogenesis in gastric cancer. Ets-1 is a useful marker for predicting the outcome for patients with gastric carcinoma, though it is not an independent prognostic indicator.

[Short-term preoperative treatment of celecoxib, a selective cyclooxygenase-2 inhibitor, on E-cadherin expression in gastric carcinoma tissues].

BACKGROUND AND OBJECTIVE: Cyclooxygenase-2 (COX-2) inhibitors have been shown to exert chemopreventive effects against gastrointestinal carcinomas. This study was to investigate the effect of celecoxib, a selective COX-2 inhibitor, on the expression of E-cadherin and serum levels of soluble E-cadherin in gastric carcinomas. METHODS: Fifty-nine gastric carcinoma patients were randomly divided into two groups: surgery group (n=22) and celecoxib plus surgery group (n=37). Patients in the surgery group underwent surgical resection after diagnosis, while patients in the celecoxib plus surgery group received oral celecoxib, 200 mg twice daily for six days before curative resection. Twenty healthy subjects were recruited as normal controls. COX-2 and E-cadherin expressions were detected by immunohistochemistry. Serum levels of soluble E-cadherin were quantitatively measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: Compared to the surgery group, the expression of COX-2 was significantly lower while that of E-cadherin was significantly higher in celecoxib plus surgery group. The concentrations of serum soluble E-cadherin before treatment were significantly higher in the surgery [(53.47+/-9.62) ng/mL] and the celecoxib plus surgery [(51.57+/-9.79) ng/mL] groups than in the control group [(37.17+/-5.38) ng/ml] (P<0.01). The soluble E-cadherin levels after surgery in both groups [(39.29+/-7.72) ng/mL and (29.29+/-8.28) ng/mL] were significantly lower than those before surgery (P<0.01). The soluble E-cadherin level on the sixth day [(44.11+/-8.36) ng/mL] was significantly lower than that before treatment in the celecoxib plus surgery group (P<0.01). CONCLUSION: Short-term preoperative treatment of celecoxib up-regulates the expression of E-cadherin in gastric carcinomas.