Prognostic Factor For Gastric Cancer Patients Research Articles

Clinical value of CagA, c-Met, PI3K and Beclin-1 expressed in gastric cancer and their association with prognosis.

Gastric cancer (GC) is the fourth most common type of malignant tumor worldwide, and causes the second highest number of cancer-associated mortalities in 2012. Gastric tumorigenesis is a multistep and multifactorial process. In the present study, tissue microarray and immunohistochemistry analysis were used to detect cytotoxin-associated gene A (CagA), c-Met, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and Beclin-1 expression in 121 GC tumors and 120 normal gastric tissues. The clinical relevance and prognostic implications of CagA, c-Met, PI3K and Beclin-1 expression in GC patients were analyzed. Furthermore, the Cox proportional hazards model was performed to indicate the independent prognostic factors for GC patients, including various clinicopathological parameters and CagA, c-Met, PI3K and Beclin-1 expression. The results indicated that CagA-positive H. pylori infection, c-Met, PI3K and Beclin-1 may have major roles in the oncogenesis, invasion and lymph node metastasis of GC. The disease-free survival rate was negatively associated with the expression of c-Met and CagA in tissues, and was positively associated with Beclin-1 expression. Overall survival was also negatively associated with the expression of c-Met and PI3K, and was positively associated with Beclin-1 expression. This indicated that c-Met and Beclin-1 may be independent and efficient biomarkers for predicting the DFS of patients with GC. Furthermore, in CagA-positive H. pylori infection-associated GC, c-Met expression was significantly upregulated and Beclin-1 expression was significantly downregulated. CagA-positive H. pylori infection therefore associated with the c-Met signaling pathway and the suppression of autophagy in the neoplasia, invasion and metastasis of GC.

Blood type AB predicts promising prognosis in gastric cancer patients with positive preoperative serum CEA.

Little is known about association between ABO blood groups and tumor markers in gastric cancer (GC) patients. The aim of the present study was to assess the prognostic value of ABO blood groups in GC patients with different levels of preoperative serum carcinoembryonic antigen (CEA).From September 2008 to April 2015, a total of 3234 GC patients who received radical gastrectomy were retrospectively analyzed. The clinicopathological characteristics including ABO blood groups and preoperative CEA were recorded. The prognostic value of ABO blood groups within different levels of serum CEA was analyzed.Overall, the ratio of male to female patients was 3.5:1; the median age was 57.4 years (range 20–87). The median overall survival (OS) for GC patients with blood type A, B, AB, and O were 52.6, 52.8, 53.8, and 53.6 months, respectively. There was no significant difference for the survival of patients among the 4 groups (P = .736). Also, no significant difference was found among the OS of the 4 blood types with negative (P = .875) and positive (P = .131) preoperative serum CEA. Further, we found that the OS of patients with positive preoperative serum CEA and blood type AB was significantly higher than that with blood type non-AB (P = .026). For patients with positive preoperative serum CEA, multivariate analysis showed that ABO blood groups were an independent prognostic factor.Blood type AB was a favorable prognostic factor for GC patients with positive preoperative serum CEA.

The tumor-stromal ratio as a strong prognosticator for advanced gastric cancer patients: proposal of a new TSNM staging system

BackgroundInsufficient attention is paid to the underlying tumor microenvironment (TME) evolution, that resulting in tumor heterogeneity and driving differences in cancer aggressiveness and treatment outcomes. The morphological evaluation of the proportion of the stroma at the most invasive part of primary tumor (tumor-stromal ratio, TSR) in cancer is gaining momentum as evidence strengthens for the clinical relevance.MethodsTissue samples from the most invasive part of the primary gastric cancer (GC) of 494 patients were analyzed for their TSR, and a new TSNM (tumor-stromal node metastasis) staging system based on patho-biological behaviors was established and assessed.ResultsTSR is a new and strong independent prognostic factor for GC patients. The likelihood of tumor invasion is increased significantly for patients in the stromal-high subgroup compared to those in the stromal-low subgroup (P = 0.011). The discrimination ability of TSR was not less than the TNM staging system and was better in patients with stages I and II GC. We integrated the TSR parameter into the TNM staging system and proposed a new TSNM staging system creatively. There were three new subgroups (IC, IIC, IIID). There were four major groups and 10 subgroups in the TSNM system. The difference in overall survival (OS) was statistically significant among all TSNM system (P < 0.005 for all). Deep analyses revealed well predictive performance of the TSNM (P < 0.001).ConclusionsThis study confirms the TSR as a TME prognostic factor for GC. TSR is a candidate TME parameter that could easily be implemented in routine pathology diagnostics, and the TSNM staging system has been established to optimize risk stratification for GC. The value of the TSNM staging system should be validated in further prospective study.

MAGE-A family is involved in gastric cancer progression and indicates poor prognosis of gastric cancer patients

BackgroundAs the best characterized CTA family members, melanoma-associated antigens (MAGE) have been reported to express in various malignant tumors. However, the expression pattern of MAGE-A family in gastric cancer (GC) specimens and their prognostic and therapeutic significance for GC patients is still unclear. Materials and methodsTissue microarray − based immunohistochemistry analysis was used to examine the expression of MAGE-A family members (including MAGE-A1, −A2, −A3, −A4, −A6, −A10, and −A12) in 86 cases of GC specimens, 20 cases of the corresponding adjacent normal gastric specimens, and 9 cases of intraepithelial neoplasia specimens. The association between MAGE-A expression and the clinicopathological parameters as well as the 5-year overall survival of GC patients was analyzed. Results54.7% of GC specimens showed positive MAGE-A expression. In the adjacent normal gastric specimens, MAGE-A was not expressed in the normal surface mucous cells, but expressed in some normal fundic glands. In addition, MAGE-A expression was also detected in intraepithelial neoplasia specimens. In GC specimens, MAGE-A expression was associated with lymph node metastasis, poor differentiation, and high clinical TNM stage. MAGE-A expression was also correlated with the poor 5-year overall survival of GC patients. However, MAGE-A expression is not an independent prognostic factor for GC patients. ConclusionsMAGE-A family may be involved in the gastric cancer progression, and their expression could be considered to improve the prognostic evaluation for GC patients.

Significant association of YAP1 and HSPC111 proteins with poor prognosis in Chinese gastric cancer patients.

Hippo-YAP1 is a tumor-suppressor signaling pathway that inhibits cell proliferation and accelerates apoptosis. However, the role of YAP1 in gastric cancer (GC) is still in dispute. Ribosomal biogenesis is closely correlated with human malignancies. HBV pre-S2 trans-regulated protein 3 (HSPC111) is a portion of an RNA-dependent complex and plays a crucial role in ribosome biosynthesis. Nevertheless, little is known about the expression and function of this factor in GC. In the present study, we evaluated the significance of YAP1 together with HSPC111 in gastric cancer. According to The Cancer Genome Atlas database, high YAP1 mRNA expression was significantly associated with poor prognosis of GC patients, and dramatically increased mRNA levels of HSPC111 are observed in GC tissues. Consistent with these findings, we detected increased expression of both YAP1 and HSPC111 in GC cell lines and clinical samples. Notably, nuclear expression of YAP1 was positively correlated with clinical stage (P = 0.041), tumor size (P = 0.023), and lymph node metastasis (P = 0.007), while HSPC111 expression was correlated with lymph node metastasis (P = 0.014). Our analyses also detected a correlation between HSPC111 expression and nuclear and cytoplasmic YAP1 in clinical samples (nuclear: r = 0.2615, P = 0.004; cytoplasm: r = −0.3721, P < 0.001) and cell lines. Finally, we showed that patients who were HSPC111- and nuclear YAP1-positive were associated with the worst prognosis (34.5 ± 4.8 months, p = 0.001), and that nuclear expression of YAP1 might act as an independent prognostic factor for GC patients.

High expression of long non-coding RNA CCAT2 indicates poor prognosis of gastric cancer and promotes cell proliferation and invasion.

Numerous studies have demonstrated that long non-coding RNAs (lncRNAs) have many biological functions and play crucial roles in various human cancers, including cancer development, metastasis and prognosis of cancer patients. CCAT2, a novel long non-coding RNA, has been identified as correlating with several different types of cancers. However, the role of lncRNA CCAT2 in gastric cancer (GC) patients is unknown. The purpose of our research was to investigate the function and prognostic significance of lncRNA CCAT2 expression in GC patients. Expression of lncRNA CCAT2 was examined in 208 paired normal and cancerous gastric tissues. Molecular and cellular techniques were used to explore the biological function of lncRNA CCAT2 in GC cells. Kaplan-Meier method and Cox proportional hazards model were used to analyze the prognostic significance of lncRNA CCAT2 expression. The results showed that lncRNA CCAT2 was upregulated in GC tissues (P=0.000), and positively correlated with TNM stage (P=0.029), lymphatic invasion (P=0.042) and nervous invasion (P=0.024) in GC patients. Furthermore, we also found that high expression of lncRNA CCAT2 was an unfavorable prognostic factor in GC patients. Silencing of lncRNA CCAT2 inhibits gastric cancer cell proliferation and invasion. lncRNA CCAT2 may serve as a tumor promoter and a new predictive prognostic factor for human gastric cancer.

Integrated Analysis Identifies Molecular Signatures and Specific Prognostic Factors for Different Gastric Cancer Subtypes

BACKGROUND: Gastric cancer (GC) is the fifth leading cause of cancer-related deaths worldwide. As an effective and easily performed method, microscopy-based Lauren classification has been widely accepted by gastrointestinal surgeons and pathologists for GC subtyping, but molecular characteristics of different Lauren subtypes were poorly revealed. METHODS: GSE62254 was used as a derivation cohort, and GSE15459 was used as a validation cohort. The difference between diffuse and intestinal GC on the gene expression level was measured. Gene ontology (GO) enrichment analysis was performed for both subgroups. Hierarchical clustering and heatmap exhibition were also performed. Kaplan-Meier plot and Cox proportional hazards model were used to evaluate survival grouped by the given genes or hierarchical clusters. RESULTS: A total of 4598 genes were found differentially expressed between diffuse and intestinal GC. Immunity- and cell adhesion–related GOs were enriched for diffuse GC, whereas DNA repair– and cell cycle–related GOs were enriched for intestinal GC. We proposed a 40-gene signature (χ2=30.71, P<.001) that exhibits better discrimination for prognosis than Lauren classification (χ2=12.11, P=.002). FRZB [RR (95% CI)=1.824 (1.115-2.986), P=.017] and EFEMP1 [RR (95% CI)=1.537 (0.969-2.437), P=.067] were identified as independent prognostic factors only in diffuse GC but not in intestinal GC patients. KRT23 [RR (95% CI)=1.616 (0.938-2.785), P=.083] was identified as an independent prognostic factor only in intestinal GC patients but not in diffuse GC patients. Similar results were achieved in the validation cohort. CONCLUSION: We found that GCs with different Lauren classifications had different molecular characteristics and identified FRZB, EFEMP1, and KRT23 as subtype-specific prognostic factors for GC patients.

243P The effects of genomic polymorphisms in one-carbon metabolism pathways on survival of gastric cancer patients received fluorouracil-based adjuvant therapy

Background Objective:5-fluorouracil(5-FU)iswidelyusedtotreatpatientswith gastric cancer (GC). However, the response rate is quite heterogeneous. The single nucleotide polymorphisms (SNPs) and their interactions ofgenes in the one-carbon metabolism (OCM) pathway, including Methylenetetrahydrofolate reductase (MTHFR), Methionine synthase reductase (MTRR), Methionine synthase (MTR), and Thymidylatesynthase(TS),significantlyaffect5-FUmetabolism. Methods In this study, 650 stage II-III patients were recruited from 1998 to 2006. Amongthem,251received5-FU-basedchemotherapyandother399patientswere untreated.TheCoxregressionanalysis,log-ranktestsandKaplan-Meierplotswere adopted in our study. Results In the chemotherapy cohort, MTRR 66 GA + GG genotypes decreased the risk ofdeath (HR = 0.657, 95% CI = 0.446-0.967, p = 0.031), however, the protect effect of MTRR 66 GA + GG disappeared when GC patients simultaneously had MTHFR 677TT + TC orMTR 2756GG + GA genotypes (HR = 0.871, 95% CI = 0.443-1.713; HR = 0.761, 95% CI = 0.451-1.287). TS 50-UTR 2R3R + 3R3R genotypes also prolongedoverallsurvivalofpatientstreatedwith5-FU(HR= 0.498, 95% CI= 0.259- 0.960,p=0.032). AndthisfavorableprognosisobviouslyenhancedwhenGCpatients simultaneously had TS 30-UTR DD + DI and TS 50-UTR 2R3R + 3R3R genotypes (HR=0.332,95%CI=0.134-0.822,p=0.046). Conclusions:OurfindingsshowedthatthepolymorphismsofMTRR66A>GandTS 5'-UTR 3R > 2R may be potential prognostic factors for GC patients receiving 5-FU- based regimens. Legal entity responsible for the study N/A Funding This work was partly supported by National 973 Basic Research Program of China(GrantNo.2013CB911300),GrantsfromNationalNaturalScienceFoundation ofChina (Grant No. 81572928) to Dr. Jinfei Chen; Disclosure All authors have declared no conflicts ofinterest.

RAD51B as a potential biomarker for early detection and poor prognostic evaluation contributes to tumorigenesis of gastric cancer.

Gastric cancer (GC) is a common and deadly disease worldwide. Outcomes of patients are poor largely due to chemoresistance or recurrence. Thus, identifying novel biomarkers to predict response to therapy and/or prognosis are urgently needed. RAD51B, a key player in DNA repair/recombination, has the potential to be a candidate oncogene and biomarker for cancer diagnosis and prognosis. However, its relationship with GC remains unclear. To evaluate clinicopathological and prognostic significance of RAD51B in GC, we examined messenger RNA (mRNA) and protein expression via quantitative real-time polymerase chain reaction (qRT-PCR) from 69 and tissue microarray from 144 GC patients, respectively. Our results showed that RAD51B mRNA expression was significantly up-regulated in tumors compared to that of matched noncancerous tissues (P<0.001). In parallel, RAD51B protein showed a mainly nucleus-staining pattern, and the positive rate in tumors and stomach atypical hyperplasia was significantly higher than that in matched noncancerous tissues (P=0.015). Moreover, high level of RAD51B protein was correlated with advanced stage (P=0.009), aggressive differentiation (P=0.022), and lymph node metastasis (P=0.001). Further, Kaplan-Meier analysis indicated that patients with high level of RAD51B expression exhibited worse overall survival compared to patients with low level (P=0.040). A multivariate Cox regression analysis suggested that RAD51B may be an independent prognostic factor for GC patients in Chinese population (P=0.004). Additionally, functional studies indicated that over-expression of RAD51B promoted cell proliferation, aneuploidy, and drug resistance, while RAD51B knockdown led to G1 arrest and sensitized cells to 5-fluorouracil (5-FU). In conclusion, RAD51B may act as an oncogene during GC progression, and its hyper-expression may be a potential biomarker for early detection and poor prognosis of GC.

The effects of genomic polymorphisms in one-carbon metabolism pathways on survival of gastric cancer patients received fluorouracil-based adjuvant therapy.

5-fluorouracil (5-FU) is widely used to treat patients with gastric cancer (GC). However, the response rate is quite heterogeneous. The single nucleotide polymorphisms (SNPs) and their interactions of genes in the one-carbon metabolism (OCM) pathway, including Methylenetetrahydrofolate reductase (MTHFR), Methionine synthase reductase (MTRR), Methionine synthase (MTR), and Thymidylate synthase (TS), significantly affect 5-FU metabolism. In this study, 650 stage II-III patients were recruited from 1998 to 2006. Among them, 251 received 5-FU treatment and other 399 patients were untreated. The Cox regression analysis, log-rank tests and Kaplan–Meier plots were adopted. In the chemotherapy cohort, MTRR 66 GA + GG genotypes decreased death risk, however, the protect effect of MTRR 66 GA + GG disappeared when GC patients simultaneously had MTHFR 677TT + TC or MTR 2756GG + GA genotypes. TS 5′-UTR 2R3R + 3R3R genotypes also prolonged overall survival of patients treated with 5-FU. And this favorable prognosis obviously enhanced when GC patients simultaneously had TS 3′-UTR DD + DI and TS 5′-UTR 2R3R + 3R3R genotypes. Our findings showed that the polymorphisms of MTRR 66 A > G and TS 5′-UTR 3R > 2R may be potential prognostic factors for GC patients receiving 5-FU.

Overexpression of long noncoding RNA HOTTIP promotes tumor invasion and predicts poor prognosis in gastric cancer.

PurposeLong noncoding RNAs have been proved to play important roles in the tumorigenesis and development of human gastric cancer (GC). Our study aims to investigate the expression and function of Homeobox A transcript at the distal tip (HOTTIP) in GC.MethodsHOTTIP expression was detected in GC tissues and cell lines by using quantitative reverse transcription polymerase chain reaction. Association between HOTTIP levels and clinicopathological factors and patient prognosis was also analyzed. MTT, flow cytometry, and transwell invasion and migration assays were used to investigate the role of HOTTIP in the regulation of biological behaviors of GC cells.ResultsHOTTIP expression was remarkably increased in GC tissues and cell lines compared with that in the normal control. Clinicopathologic analysis revealed that high HOTTIP expression correlated with larger tumor size, deeper invasion depth, positive lymph node metastasis, advanced TNM stage, and shorter overall survival. Multivariate regression analysis identified HOTTIP overexpression as an independent unfavorable prognostic factor in GC patients. Moreover, HOTTIP downregulation by si-HOTTIP transfection impaired GC cell proliferation, promoted cell apoptosis, and reduced cell invasion and migration.ConclusionThese findings suggested that HOTTIP may contribute to GC initiation and progression, and would be not only a novel prognostic marker but also a potential therapeutic target for this disease.

High Infiltration of Tumor-Associated Macrophages Influences Poor Prognosis in Human Gastric Cancer Patients, Associates With the Phenomenon of EMT.

Tumor-associated macrophages (TAMs) are associated with poor prognosis in numerous human cancers and play important roles in tumor progression. Epithelial-mesenchymal transition (EMT) contributes to invasion and metastasis in cancer. However, the associations between TAMs and EMT are not clear in gastric cancer (GC). The present study was designed to investigate the effects of TAMs on EMT in human GC.TAMs marker CD68 and EMT-related proteins were detected by immunohistochemistry (IHC) in human GC tissues and their clinical significance were evaluated.A high level of infiltration of TAMs was associated with aggressive characteristics of tumor and an independent poor prognostic factor in human GC tissues. Infiltration of TAMs was also associated with EMT-related proteins in human GC tissues.Our findings suggest that the high level of infiltration TAMs was associated with aggressive features of GC and is an independent poor prognostic factor in GC patients. TAMs are associated with EMT induction in human GC tissues. The level of TAMs infiltration may be used as a prognostic factor and even a therapeutic target in GC.

Positive impact of adding No.14v lymph node to D2 dissection on survival for distal gastric cancer patients after surgery with curative intent.

D2 lymphadenectomy has been increasingly regarded as standard surgical procedure for advanced gastric cancer (GC), while the necessity of No.14v lymph node (14v) dissection for distal GC is still controversial. A total of 920 distal GC patients receiving at least a D2 lymph node dissection in Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital were enrolled in this study, of whom, 243 patients also had the 14v dissected. Other 677 patients without 14v dissection were used for comparison. Forty-five (18.5%) patients had 14v metastasis. There was no significant difference in 3-year overall survival (OS) rate between patients with and without 14v dissection. Following stratified analysis, in TNM stages I, II, IIIa and IV, 14v dissection did not affect 3-year OS; in contrast, patients with 14v dissection had a significant higher 3-year OS than those without in TNM stages IIIb and IIIc. In multivariate analysis, 14v dissection was found to be an independent prognostic factor for GC patients with TNM stage IIIb/IIIc disease [hazard ratio (HR), 1.568; 95% confidence interval (CI): 1.186-2.072; P=0.002]. GC patients with 14v dissection had a significant lower locoregional, especially lymph node, recurrence rate than those without 14v dissection (11.7% vs. 21.1%, P=0.035). Adding 14v to D2 lymphadenectomy may be associated with improved 3-year OS for distal GC staged TNM IIIb/IIIc.

Prognostic value of ABO blood group in patients with gastric cancer

BackgroundPrevious studies have shown a link between the ABO blood groups and prognoses for several types of malignancies. However, little is known about the relationship between the ABO blood groups and prognosis in patients with gastric cancer (GC). The aim of this study was to investigate the prognostic performance of ABO blood groups in patients with GC. MethodsA total of 1412 GC patients who had undergone curative intent surgery between January 2005 and January 2010 participated in the present study. A prognostic nomogram was constructed to improve the predictive capacity for patients with gastrectomy using R software, and its predictive accuracy was determined by the concordance index (c-index). ResultsThe median follow-up period of the 1412 GC patients was 44 mo with 809 alive. Non-AB blood groups were associated with significantly decreased overall survival in GC patients (hazard ratio = 2.59; 95% confidence interval = 1.74–3.86, P < 0.001), but patients in the group AB had a better prognosis than those in the non-AB blood groups. Meanwhile, group A had the worst prognosis among all the blood groups (hazard ratio = 3.14; 95% confidence interval = 2.09–4.72; P < 0.001). In addition, our constructed nomogram, superior to that of the traditional AJCC stage system (c-index: 0.69), could more accurately predict overall survival (c-index: 0.78) in GC patients who had undergone gastrectomy. ConclusionsThe blood group AB is a favorable prognostic factor for GC patients, but the blood group A is an adverse prognostic factor for patients with gastrectomy. Further prospective studies are warranted to confirm this relationship.

CCR6 overexpression predicted advanced biological behaviors and poor prognosis in patients with gastric cancer.

CCR6 expression is deregulated in some human malignancies and may be involved in the tumor progression. The aim of the present study was to determine the CCR6 expression in gastric cancer (GC) and to clarify its clinical significance. We used western blotting to examine CCR6 protein expression in GC tissues and matched adjacent non-tumor tissues. Immunohistochemistry was performed on a large cohort of 372 postoperative GC samples. Chi-square test, Kaplan-Meier analysis and Cox regression model were used to analyze the data. Upregulated CCR6 protein expression was observed in the GC tissues by western blotting compared with the adjacent non-cancerous gastric tissues. High CCR6 expression was detected in 56.5% (210/372) samples and significantly associated with the extracapsular extension of the tumor, tumor relapse and poor overall survival in GC (P<0.001). Further analysis demonstrated that the CCR6 expression level stratified the patient outcome in stage II, stage III, T3/4, N positive and poorly differentiated/undifferentiated tumor subgroups. The Cox regression analysis showed that high expression of CCR6 was an independent prognostic factor for GC patients. CCR6 expression may be a novel biomarker for predicting clinical outcomes for GC patients.

Overexpression of the chemokine receptor CXCR3 and its correlation with favorable prognosis in gastric cancer

Chemokine receptor, CXCR3, has been increasingly reported to be involved in tumorigenesis and tumor progression, but limited data are available regarding the expression of CXCR3 in gastric cancer (GC). In the present study, the expressions of CXCR3 and its variants were detected in 96 GC and corresponding nontumor gastric tissues by immunohistochemical staining, in 40 freshly frozen GC and nontumor gastric tissues by reverse-transcription polymerase chain reaction and quantitative real-time polymerase chain reaction, and in 10 freshly frozen GC and nontumor gastric tissues by Western blotting. Results revealed that an overexpression of CXCR3 occurs in GC tissues as compared to the nontumor gastric tissues. High level of CXCR3 expression was found to be inversely associated with invasion depth and metastasis (P = .030 and P = .019, respectively) and directly associated with improved overall survival (log-rank test, P < .001). Furthermore, multivariate analysis showed that high CXCR3 expression acts an independent prognostic factor for GC patients (hazard ratio, 0.379 [0.196-0.734]; P = .004). The messenger RNA expression of both the CXCR3 variants, CXCR3-A and CXCR3-B, were up-regulated in GC tissues (P = .006 and P = .002, respectively), although CXCR3-B messenger RNA expression was significantly higher than CXCR3-A, with an average CXCR3-B to CXCR3-A ratio of 1.80. CXCR3-B protein expression was also up-regulated in GC tissues (P = .023). In conclusion, our study suggested a potential use of CXCR3 overexpression as a prognostic marker for GC and involvement of the up-regulation of CXCR3-B in favorable prognosis of GC patients.

High expression of transforming acidic coiled coil-containing protein 3 strongly correlates with aggressive characteristics and poor prognosis of gastric cancer.

Transforming acidic coiled coil-containing protein3 (TACC3) is well understood to regulate mitotic spindle dynamics and centrosome integrity during mitosis. TACC3 has been suggested to be deregulated in a variety of human malignancies and may be involved in the process of cancer progression. The aim of the present study was to determine the status of TACC3 expression in gastric cancer (GC) and to clarify its clinical/prognostic significance. In the present study, we applied quantitative PCR (qPCR) and western blotting to examine TACC3 mRNA/protein expression in paired GC tissues and matched adjacent non-malignant tissues. Immunohistochemistry (IHC) was performed on a large cohort of 186 postoperative GC samples. Chi-square test, Kaplan-Meier analysis and Cox regression modelling were used to analyse the data. Upregulated mRNA and protein expression levels of TACC3 were observed in the majority of the GC tissues based on qPCR and western blotting compared to the adjacent non-cancerous gastric tissues. Specific IHC staining for TACC3 was predominantly identified in the cytoplasm of the cancer cells. A high expression of TACC3 was detected in 102 of the 186 (54.8%) tissue samples and was significantly associated with the extracapsular extension of the tumour (P<0.001), tumour relapse (P<0.001) and shortened overall survival in GC (P<0.001). Further analysis demonstrated that the TACC3 expression level stratified the patient outcome in stage II (P=0.040), stage III (P<0.001), T3/4 (P<0.001), N positive (P<0.001) and poorly differentiated/undifferentiated tumour subgroups (P<0.001). The Cox regression analysis suggested that a high expression of TACC3 was an independent prognostic factor for GC patients. The measurement of TACC3 protein expression may be beneficial for predicting clinical outcomes for GC patients.

Activated Pak4 expression correlates with poor prognosis in human gastric cancer patients

Despite considerable advances in gastrectomy and chemotherapy, the prognosis of gastric cancer (GC) has not noticeably improved due to lymph node or distant metastases. P21-activated serine/threonine kinase 4 (Pak4) plays an important role in cell morphology and cytoskeletal reorganization-both prerequisite steps for cell migration. However, it is still unclear if activated Pak4 (p-Pak4) is related to prognosis in GC patients. In our study, the level of p-Pak4 in 95 GC tissue specimens was examined by immunohistochemistry (IHC). We observed significant correlation between the level of p-Pak4 and grosstype (advanced stage GC vs. early stage GC, P = 0.04). Moreover, GC patients with higher p-Pak4 levels had a poorer prognosis than those with lower p-Pak4 levels (17 vs. 38 months, P = 0.001). Multivariate analysis showed that high phosphorylation level of Pak4, advanced stage GC, and lymph node metastasis were independent prognostic factors for GC patients (p-Pak4, P = 0.026; advanced stage GC, P = 0.030; lymph node metastasis, P = 0.016). In addition, in vitro assays indicated that knockdown of Pak4 accompanied with decreased p-Pak4, inhibited cell migration via downregulation of the traditional downstream signaling pathways of Pak4, LIMK1, and cofilin. In conclusion, this report reveals that high level of p-Pak4 correlates with poor prognosis in GC, thereby suggesting that p-Pak4 might be a potential prognostic marker for GC.

Expression of pyruvate dehydrogenase is an independent prognostic marker in gastric cancer

To investigate the expression and prognostic role of pyruvate dehydrogenase (PDH) in gastric cancer (GC). This study included 265 patients (194 male, 71 female, mean age 59 years (range, 29-81 years) with GC who underwent curative surgery at the First Affiliated Hospital of China Medical University from January 2006 to May 2007. All patients were followed up for more than 5 years. Patient-derived paraffin embedded GC specimens were collected for tissue microarrays (TMAs). We examined PDH expression by immunohistochemistry in TMAs containing tumor tissue and matched non-neoplastic mucosa. Immunoreactivity was evaluated independently by two researchers. Overall survival (OS) rates were determined using the Kaplan-Meier estimator. Correlations with other clinicopathologic factors were evaluated by two-tailed χ(2) tests or a two-tailed t-test. The Cox proportional-hazard model was used in univariate analysis and multivariate analysis to identify factors significantly correlated with prognosis. Immunohistochemistry showed that 35.47% of total cancer tissue specimens had cytoplasmic PDH staining. PDH expression was much higher in normal mucosa specimens (75.09%; P = 0.001). PDH expression was correlated with Lauren grade (70.77% in intestinal type vs 40.0% in diffuse type; P = 0.001), lymph node metastasis (65.43% with no metastasis vs 51.09% with metastasis; P = 0.033), lymphatic invasion (61.62% with no invasion vs 38.81% with invasion; P = 0.002), histologic subtypes (70.77% in intestinal type vs 40.0% in diffuse type; P = 0.001) and tumor-node-metastasis (TNM) stage (39% in poorly differentiated vs 65.91% in well differentiated and 67.11% in moderately differentiated; P = 0.001) in GC. PDH expression in cancer tissue was significantly associated with higher OS (P < 0.001). The multivariate analysis adjusted for age, Lauren classification, TNM stage, lymph node metastasis, histological type, tumor size, depth of invasion and lymphatic invasion showed that the PDH expression in GC was an independent prognostic factor for higher OS (HR = 0.608, 95%CI: 0.504-0.734, P < 0.001). Our study indicated that PDH expression is an independent prognostic factor in GC patients and that positive expression of PDH may be predictive of favorable outcomes.

Significance of the preoperative neutrophil-to-lymphocyte ratio in the prognosis of patients with gastric cancer.

To investigate the significance of the preoperative neutrophil-to-lymphocyte ratio (NLR) in the prognosis of patients with gastric cancer (GC). The clinical data of 291 GC patients were analysed retrospectively; these patients were divided into two groups according to their preoperative NLR: a high-NLR group (NLR ≥ 3.5, 131 cases) and a low-NLR group (NLR < 3.5, 160 cases). The clinicopathological characteristics and five-year survival rates of the two groups were compared. The NLR and other clinicopathological factors were subjected to univariate and multivariate survival analysis to evaluate the effects of the NLR on the prognosis of GC patients. The lowest preoperative NLR among the 291 patients was 0.56, whereas the highest preoperative NLR was 74.5. The mean preoperative NLR was 5.99 ± 8.98. Age, tumour size, T staging, tumour-node-metastasis (TNM) staging and platelet count were significantly different between the high- and low-NLR groups (P < 0.05). The five-year survival rate of the high-NLR group was 17.0%, which was significantly lower than that of the low-NLR group (43.6%; 17.0% vs 43.6%, P < 0.05). The univariate analysis results showed that the five-year survival rate was related to age, tumour size, T staging, N staging, TNM staging, carcinoembryonic antigen value and NLR (P < 0.05). Multivariate analysis results showed that the NLR was an independent risk factor that likely affected the five-year survival rate of GC patients (P = 0.003, HR = 0.626, 95%CI: 0.460-0.852). The preoperative NLR could be used as a prognostic factor for GC patients; in particular, a high NLR corresponded to poor prognosis of GC patients.