Guanine nucleotide binding protein-like 3 is a potential prognosis indicator of gastric cancer

Guanine nucleotide binding protein-like 3 (GNL3) is a GIP-binding nuclear protein that has been reported to be involved in various biological processes, including cell proliferation, cellular senescence and tumorigenesis. This study aimed to investigate the expression level of GNL3 in gastric cancer and to evaluate the relationship between its expression and clinical variables and overall survival of gastric cancer patients. The expression level of GNL3 was examined in 89 human gastric cancer samples using immunohistochemistry (IHC) staining. GNL3 in gastric cancer tissues was significantly upregulated compared with paracancerous tissues. GNL3 expression in adjacent non-cancerous tissues was associated with sex and tumor size. Survival analyses showed that GNL3 expression in both gastric cancer and adjacent non-cancerous tissues were not related to overall survival. However, in the subgroup of patients with larger tumor size (≥ 6 cm), a close association was found between GNL3 expression in gastric cancer tissues and overall survival. GNL3-positive patients had a shorter survival than GNL3-negative patients. Our study suggests that GNL3 might play an important role in the progression of gastric cancer and serve as a biomarker for poor prognosis in gastric cancer patients.     

Expression of Tim-3 in gastric cancer tissue and its relationship with prognosis

As a negative regulatory molecule, T-cell immunoglobulin–and mucin domain-3 (Tim-3) plays a crucial role in the tumor immunological tolerance. In the present study, we aimed to determine the Tim-3 expression in gastric cancer tissue and its relationship with clinicopathological parameters and prognosis. The Tim-3 expression was assessed in 52 gastric cancer specimens and 15 gastritis tissues by flow cytometry, and gastritis tissues served as the control. As a result, we found that the Tim-3 expressions on CD4⁺T cells and CD8⁺T cells in gastric cancer tissue was significantly higher than those in gastritis tissue (P=0.022, P=0.047, respectively). The median expression level of Tim-3 on CD4⁺T cells were significantly correlated with clinicopathological parameters, such as tumor size, lymph node metastasis, the depth of tumor invasion and TNM staging (P=0.042, P=0.026, P=0.001, P=0.003, respectively), while it was not correlated with sex, age and histological subtype (all P>0.05). In CD8⁺T cells, the Tim-3 expression was relevant to tumor invasion and TNM staging (P=0.035, P=0.017, respectively), while it was irrelevant to other clinicopathological parameters (all P>0.05). Additionally, Kaplan-Meier survival curves showed that the median overall survival time of patients with lower Tim-3 expression was greater than that of patients with higher Tim-3 expression in CD4⁺T cells and CD8⁺T cells (χ²=18.036, P<0.001 and χ²=18.036, P<0.001, respectively). Moreover, the multivariate analysis revealed that the Tim-3 expression and TNM stage were independent prognostic factors for gastric cancer patients (P=0.029, P=0.043 and P=0.003, respectively). These results suggest that Tim-3 played an important role in the development and progression of gastric cancer, and it could be used as an independent prognostic factor for gastric cancer patients.     

Clinicopathological characteristics and prognosis of alpha-fetoprotein positive gastric cancer in Chinese patients

Purpose: This study aimed to review the clinicopathological, histochemical, and prognostic features of Alpha-Fetoprotein (AFP) positive gastric cancer. Patients and methods: Six hundred and fifty one patients with gastric cancer who underwent gastrectomy between January 2009 and December 2012 at The First Hospital of Jilin University were enrolled in the study. Among them, 45 patients were identified as AFP positive gastric cancer. The clinicopathologic characteristics and prognosis of the AFP positive gastric cancer patients were analyzed. Results: Among the 45 AFP positive patients, serum levels of AFP were < 100 µg/L in nine patients. The histological classification of 45 patients was as follows: hepatoid type, 25 (55.6%) cases; fetal gastrointestinal type, 12 (26.7%) cases; yolk sac tumor type, 2 (4.4%) cases; and mixed type, 6 (13.3%) cases. Twenty nine (64.4%) cases were AFP positive by immunohistochemical analysis; we found no significant difference in AFP positivity and histologic type. However, the differences in the number of metastasis lymph nodes, the maximum tumor diameter, pathological stage, vascular invasion and liver metastasis between the AFP positive group and the negative group were significant. At the same T stage, the liver metastasis status of the AFP positive group was higher than that of the negative group. The AFP positive group had a much poorer prognosis than the negative group. Conclusion: AFP positive gastric cancer is associated with aggressive behavior and poorer prognosis compared to that of AFP negative gastric cancer.     

Decreased expression of SEMA3A is associated with poor prognosis in gastric carcinoma

Background/purpose: SEMA3A (semaphorin-3A), is a secreted protein that belongs to the semaphorin family and can function as both a chemoattractive agent or a chemorepulsive agent. SEMA3A has been shown to be a tumor suppressor in various cancers. This study investigated the expression of SEMA3A in gastric cancer and its prognostic value for gastric cancer patients. Methods: We examined the expression of SEMA3A in paired cancerous and matched adjacent noncancerous gastric mucosa tissues by real-time quantitative RT-PCR (qRT-PCR) and western blotting. In vitro, we evaluate the effects of SEMA3A on gastric cancer cell proliferation and migration by MTT, transwell and wound-healing assays. Furthermore, we analyzed SEMA3A expression in 128 patients who underwent resection procedures using immunohistochemistry. The relationships between the SEMA3A expression levels, the clinicopathological factors, and patient survival were investigated. Results: Our results revealed decreased SEMA3A mRNA (P = 0.0037) and protein (P = 0.033) expression in tumor tissue samples compared with matched adjacent non-tumorous tissue samples. Overexpression of SEMA3A inhibits gastric cancer cell proliferation and migration in vitro. Immunohistochemical staining data showed that SEMA3A expression was significantly decreased in 54.68% of gastric cancer cases. In addition, the chi-square test revealed that low SEMA3A expression was significantly correlated with poor differentiation (P = 0.015), Vascular invasion (P = 0.001), depth of invasion (P < 0.001), lymph node metastasis (P = 0.029), distant metastasis (P = 0.002) and advanced TNM stage (P = 0.003). SEMA3A expression was positively correlated with clinical TNM stage, that suggested the more advanced clinical TNM stage corresponding to the lower expression level of SEMA3A (r_s = -0.322, P < 0.001) by Spearman rank correlation analysis. Kaplan-Meier survival analysis demonstrated that low expression of SEMA3A was significantly correlated with a poor prognosis for gastric cancer patients (P < 0.001). The multivariate analysis revealed that SEMA3A expression was an independent prognostic factor of the overall survival rate of patients with gastric cancer. Conclusion: SEMA3A expression decreased significantly as gastric cancer progressed and metastasized, suggesting that SEMA3A might serve as a candidate tumor suppressor and a potential prognostic biomarker in gastric carcinogenesis.     

STAT3 activation in tumor cell-free lymph nodes predicts a poor prognosis for gastric cancer

STAT3 is constitutively activated in many human cancers including gastric cancer and plays crucial roles in modulating cancer cell proliferation, survival, metastasis as well as the microenvironment of pre-metastatic niches. Accumulating evidence has implicated STAT3 as a promising target for cancer therapy and it has been well established that tumor cell metastasized to lymph node is associated with poor prognosis. However, little is known about the relation between STAT3 activation in tumor cell-free lymph nodes and patient clinical outcomes. The objective of the current study was to investigate the role of STAT3 activity in tumor cell-free lymph nodes in tumor progression and prognosis for gastric cancer patients. Immunohistochemical analyses for p-STAT3, Ki-67, CD68 and Bcl-xL were performed in tumor cell-free lymph nodes from 60 gastric cancer patients. Survival analysis was conducted by using the Kaplan-Meier method. Immunohistochemical analyses showed that hyperactivity of STAT3 in tumor cell-free lymph nodes was significantly associated with tumor recurrence, and STAT3 activation pattern coincides with expression Ki-67, CD68, Bcl-xL. Survival analysis revealed that persistent STAT3 activation in uninvolved lymph nodes was positively associated with poor overall survival (P<0.05). These findings suggest that STAT3 activation in tumor-free lymph nodes is involved in the pathogenesis and metastasis of gastric cancer and that elevated STAT3 activity in lymph nodes prior to tumor cell arrival may indicate a poorer prognosis. These clinical studies support our findings in mouse tumor models showing that STAT3 activation is crucial for pre-metastatic niche formation and metastasis.     

Increased MT2-MMP expression in gastric cancer patients is associated with poor prognosis

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that contribute to tumorigenesis and metastasis due to their ability to degrade the extracellular matrix (ECM) and basement membrane. In despite of many reports in other solid tumors, the role of membrane type-2 MMP (MT2-MMP) in gastric cancer (GC) remains to be elucidated. The aim of this study was to investigate MT2-MMP expression in human GC tissue microarray (TMA) samples using immunohistochemistry (IHC). We found that MT2-MMP expression in tumor tissues was significantly higher compared to peritumoral tissues (P < 0.01). However, there were no statistically significant differences between MT2-MMP expression and clinicopathological parameters. In addition, univariate and multivariate Cox regression analysis showed GC patients with high MT2-MMP expression have poor overall survival (OS) compared to patients with low MT2-MMP expression (P = 0.013, P = 0.040, respectively). In conclusion, MT2-MMP is involved in GC invasion and metastasis and may serve as an independent prognostic factor for GC patients.     

Low CA II expression is associated with tumor aggressiveness and poor prognosis in gastric cancer patients

Background: Carbonic anhydrase II is present in normal gastric mucosa; thus, this study aimed to investigate whether its expression persisted in neoplastic gastric tissues, as well as its prognostic value for gastric cancer patients. Methods: The protein CA II expression pattern was retrospectively analyzed by immunohistochemistry in 181 gastric cancer patients who had undergone gastrectomy. The relationship between the CA II expression level and clinicopathological parameters was investigated. Survival analysis according to CA II expression was measured by Kaplan-Meier analysis. Univariate and multivariate Cox regression analyses were used to evaluate the prognostic value of CA II expression. Results: CA II expression was significantly decreased in gastric cancer tissues compared with normal stomach mucosa. Low expression was significantly associated with tumor size, depth of invasion, lymph node involvement, distant metastasis and TNM stage, and it predicted poor survival in gastric cancer patients. Moreover, CA II was an independent prognosis indicator for the overall survival of gastric cancer patients. Conclusions: The down-regulation of CA II expression was observed in gastric cancer and may serve as an independent prognostic factor for the overall survival of gastric cancer patients.     

FHIT gene in gastric cancer: association with tumour progression and prognosis

The FHIT (fragile histidine triad) gene has been recently identified and cloned at chromosome 3p14.2 including FRA3B, the most common fragile site in the human genome. FHIT is suggested to be a candidate tumour suppressor gene in gastrointestinal tract tumours. To elucidate the role of the FHIT gene in gastric cancer, a total of 133 curatively R0-resected gastric carcinomas were investigated for loss of heterozygosity (LOH) at 3p14.2, using four polymorphic microsatellite loci (D3S1300, D3S1313, D3S1481, and D3S1234). LOH of the FHIT gene affecting at least one of the investigated loci was observed in 20 of 123 informative tumours (16·3 per cent). The presence of LOH was correlated neither with major prognostic factors such as pT category, pN category or vascular invasion, nor with histological type or grade of differentiation of the tumours. In addition, there were no differences in the prognosis between patients with gastric carcinomas showing LOH at the FHIT gene and patients with tumours lacking LOH at the FHIT gene. These findings suggest that LOH of the FHIT gene represents an event in the tumourigenesis of only a small subset of gastric carcinomas and does not correlate with tumour progression or prognosis. Copyright © 1999 John Wiley & Sons, Ltd.     

Decreased expression of histone deacetylase 10 predicts poor prognosis of gastric cancer patients

Aberrant expression of histone deacetylase (HDACs) was associated with carcinogenesis and progression of various tumors. However, the association of HDAC10 with clinical outcomes in gastric cancer patients is unclear. Thus, the objective of the current study was to evaluate the association of expression level of HDAC10 with clinicopathologic factors and prognosis of patients with gastric cancer. The expression level of HDAC10 in 179 paraffin-embedded gastric cancer tissue specimens was examined by immunohistochemistry (IHC). As a result, we found that expression of HDAC10 in gastric cancer was significantly decreased in gastric cancer tissues as compared with adjacent tissues (51.4% vs. 87.3%, P < 0.001). HDAC10 expression was significantly correlated with gender (P = 0.023), tumor size (P = 0.015), histological grade (P = 0.009), tumor invasion (P = 0.033), lymph node metastatic status (P = 0.019) and tumor stage (P = 0.004), but not correlated with age and lauren classification (all P > 0.05). Kaplan-Meier survival curves showed that the overall survival rate was significantly lower in the patients with low expression of HDAC10 compared with those patients with high HDAC10 (P < 0.001). Moreover, multivariate analysis revealed that HDAC10 expression was an independent prognostic factor for gastric cancer patients (P = 0.001). These results suggest that HDAC10 expression could see as a prognosis marker for gastric cancer patients.     

DNA methyltransferase 3a rs1550117 genetic polymorphism predicts poor survival in gastric cancer patients

DNA methyltransferase 3a (DNMT3a) have been suggested to play a crucial role in human cancer prognosis. Single nucleotide polymorphisms (SNPs) in DNMT3a genes may have an impact on the prognosis of cancers. This study aimed to investigate the association between SNPs of DNMT3a gene and prognosis of gastric cancer (GC). Two sites of DNMT3a SNPs, rs1550117 and rs13420827 were selected and genotyped using TaqMan assay in 447 GC patients who received gastrectomy. Effects of genotypes on clinical outcomes of GC were calculated by Kaplan-Meier survival analysis and Cox regression model. We found that the AG or AA genotype of rs1550117 was associated with significantly poorer survival and increased death risk of GC compared with GG genotype (dominant model: HR=1.35, 95% CI=1.01-1.80, P=0.043). Further multivariate Cox regression analysis revealed that in addition to the known factors including male, larger tumor sizes and high clinical stage, rs1550117 variant was an independently predictive factor for survival in GC patients. No significant association was found between rs13420827 genetic variants and GC prognosis. Our findings first demonstrated that DNMT3a rs1550117 polymorphism may be a potential biomarker in predicting overall survival of GC patients.     

High tissue expression of tumour-associated trypsin inhibitor (TATI) associates with a more favourable prognosis in gastric cancer

AIMS: The tumour-associated trypsin inhibitor (TATI) is a 6-kDa protease inhibitor with potential inhibitory effects on tissue degradation. In serum, increased levels have been associated with adverse prognosis in different forms of cancer. We assessed the tumour tissue expression and prognostic value of TATI in a surgically treated, single-institution series of patients with gastric cancer. METHODS AND RESULTS: Using a monoclonal anti-TATI antibody, immunohistochemistry was performed on formalin-fixed paraffin-embedded tumour specimens from 336 patients. TATI expression was observed in 265 (79%) of the tumours. There was a significant association between high TATI expression and low stage (P = 0.007), superficial tumours (P = 0.005), and absence of nodal (P = 0.015) and of distant metastases (P = 0.022). In univariate analysis, patients with high TATI expression had a significantly more favourable 5-year cumulative survival compared with patients with negative to moderate immunostaining (43% and 28%, respectively, P = 0.006). On multivariate survival analysis stratified for estimated cure of surgery, stage (P < 0.0001) and age (P = 0.022) at the time of surgery were independent prognostic factors. CONCLUSIONS: High TATI expression in tumour tissue was detected more frequently in patients with early-stage gastric cancer and seems to correlate with a favourable outcome.     

FOXO3a蛋白在缺氧小鼠脑组织中的表达

目的:探讨叉头框蛋白O3a(FOXO3a)在缺氧小鼠大脑组织中的表达.方法:16只SPF级3月龄C57小鼠随机分为对照组(control)和缺氧组(hypoxia).两组小鼠分别接受常氧浓度环境及低氧环境处理1 h,应用Western Blot法定量检测FOXO3a蛋白的表达水平;应用免疫荧光染色技术检测FOXO3a蛋...     

Up-regulation of Tim-3 is associated with poor prognosis of patients with colon cancer

Tim-3 (T cell immunoglobulin and mucin domain 3), belonging to the member of the novel Tim family, has been confirmed that it plays a critical negative role in regulating the immune responses against viral infection and carcinoma. Recently, it has also been reported that the over-expression of Tim-3 is associated with poor prognosis in solid tumors. However, the role of Tim-3 in colorectal cancer remains largely unknown. In the current study, we aim to investigate the expression of Tim-3 in colorectal carcinoma and discuss the relationship between Tim-3 expression and colon cancer prognosis, thus speculating the possible role of Tim-3 in colon cancer progression. Colon cancer tissues and paired normal tissue were obtained from 201 patients with colon cancer for preparation of tissue microarray. Tim-3 expression was evaluated by immunohistochemical staining. The Tim-3 expression level was evaluated by q-RT-PCR, western blot and immunocytochemistry in four colon cancer cell lines (HT-29, HCT116, LoVo, SW620). Tim-3 was expressed in 92.5% tumor tissue samples and 86.5% corresponding normal tissue samples. Expression of Tim-3 was significantly higher in tumor tissues than in normal tissues (P < 0.0001). Tim-3 expression in colon cancer tissues is in correlation with colon cancer lymphatic metastasis and TNM (P < 0.0001). Multivariate analysis demonstrated that Tim-3 expression could be a potential independent prognostic factor for colon cancer patients (P < 0.0001). Kaplan-Meier survival analysis result showed that patients with higher Tim-3 expression had a significantly shorter survival time than those with lower Tim-3 expression patients. Our results indicated that Tim-3 might participate in the tumorgenesis of colon cancer and Tim-3 expression might be a potential independent prognostic factor for patients with colorectal cancer.     

CPEB4和VEGF-C在胃癌中的表达及其临床意义

目的:分析胞质多聚腺苷酸化成分结合蛋白4(cytoplasmic polyadenylation element binding protein 4,CPEB4)和血管内皮生长因子(vascular endothelial growth factor-C,VEGF-C)在胃癌中的表达及其与临床病理因素及预后的关系.方法:Western印迹检测胃癌细胞株及正常胃黏膜细胞株中蛋白的表达,免疫组织化学分析胃癌石蜡标本蛋白的表达,运用统计学方法研究蛋白表达与胃癌临床病理的相关性.运用相关分析分析蛋白表达与临床相关性,Log-rank单因素分析和Cox多因素分析对预后进行分析.结果:Western印迹检测CPEB4和VEGF-C蛋白在GES-1胃黏膜细胞株相对表达量明显低于HGC-27,SGC7901和MGC803胃癌细胞株,差异具有统计学意义(P<0.05).CPEB4阳性表达率为55.0%,VEGF-C阳性表达率为41.4%;相关分析显示肿瘤大小、肿瘤部位和T分期与CPEB4表达相关,肿瘤大小和N分期与VEGF-C表达密切相关,预后生存Cox多因素分析结果显示分化程度、淋巴结转移N分期、CPEB4表达与VEGF-C表达是胃癌患者的独立预后因素.结论:CPEB4和VEGF-C表达在胃癌的侵袭中起重要作用,其表达为胃癌预后独立因素,可作为胃癌预后指标.     

Identification of long noncoding RNA TC0101441 as a novel biomarker for diagnosis and prognosis of gastric cancer

The present work aimed to explore the prognostic values of lncRNA TC0101441 (TC0101441) in patients with gastric cancer (GC). The expression of TC0101441 in a total of 159 GC specimens and matched normal specimens was detected by quantitative RT-PCR. ROC assays were conducted to determine the diagnostic value of TC0101441 expression in GC patients. The association of TC0101441 expression with clinical characteristics of 159 patients was analyzed using chi-square test. Kaplan-Meier methods were employed to determine the prognostic value of TC0101441 expression in the survival rate of GC patients. Multivariate Cox regression assays were used to identify whether TC0101441 could be a prognostic biomarker for GC patients. We found that TC0101441 expression was significantly increased in GC specimens compared to that in the normal specimens (P < 0.01). High TC0101441 expression was correlated with lymphatic metastasis (P = 0.027) and TNM stage (P = 0.015). TC0101441 could distinguish GC specimens from adjacent normal gastric specimens with an area under the receiver operating characteristic curve (AUC) of 0.8082. Survival data revealed that patients with high TC0101441 expression had worse overall survival (P = 0.0009) and disease-free survival (P < 0.0001) rates than those with low TC0101441 expression. Multivariate assays showed that TC0101441 expression was an independent biomarker for GC patients. The present study suggested that TC0101441 expression was increased in GC and may be aprognostic and diagnostic biomarker for GC.     

Comparison of histopathological and flow cytometric parameters in prediction of prognosis in gastric cancer

Flow cytometric analysis was performed retrospectively on material from 76 patients having potentially curative resection for gastric carcinoma between 1968 and 1984. The prognostic significance of DNA aneuploidy was compared with that of conventional histological grading and staging of the tumour. The presence of DNA aneuploidy was associated with a significantly poorer prognosis when compared with diploid tumours (P less than 0.02), but was not found to be predictive of survival when the presence of lymph node metastases (P less than 0.0001) and resection margin involvement (P less than 0.003) were allowed for using multiple regression analysis. When intestinal and diffuse types of gastric carcinoma were analysed separately, DNA aneuploidy was associated with a significantly shorter survival only in patients with intestinal type tumours.