Independent Prognostic Factor In Gastric Cancer Research Articles

Significant association of DIRC1 overexpression with tumor progression and poor prognosis in gastric cancer.

DIRC1, Disrupted in Renal Cancer 1, was identified as a breakpoint-spanning gene in a chromosomal translocation, which was associated with the onset and progression of some cancers. However, the expression in human gastric cancer (GC) and the role of DIRC1 in human gastric tumorigenesis are unknown. Thereby, the main purpose of this study was to unearth the association of DIRC1 with GC. By analyzing The Cancer Genome Atlas (TCGA) datasets, the expression of DIRC1 in GC and normal gastric tissues were compared. Besides, its association with clinicopathological significance, overall survival (OS) and independent prognosis were analyzed by Pearson's x2 test, Kaplan-Meier method and Cox proportional hazards model, respectively. Functionally, the knockdown of DIRC1 was performed by siRNA method; moreover, its effects on the proliferation and metastasis of GC cells were examined by CCK-8 and transwell assays. Furthermore, the key markers of protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling were tested by Western blot assay. The results showed that high expression of DIRC1 was found in GC tissues compared with normal gastric tissues. High expression of DIRC1 was associated with more cases of severer tumor malignancy and shorter OS; besides, high-level of DIRC1 was suggested to be an independent prognostic factor for GC. Furthermore, the knockdown of DIRC1 inhibited SGC-7901 GC cells proliferation, migration and invasion. Mechanically, the activity of AKT/mTOR signaling was suppressed by the knockdown of DIRC1. These findings offer clinical associations and an in vitro evidence showing that the knockdown of DIRC1 impeded the GC carcinogenicity possibly via suppression of AKT/mTOR signaling. This work might provide a potential therapeutic target for GC treatment.

Gene regulatory network construction identified NFYA as a diffuse subtype-specific prognostic factor in gastric cancer.

Lauren classification is a pathology-based gastric cancer (GC) subtyping system, which is widely used in the clinical treatment of patients with GC. However, genome- scale molecular characteristics to distinguish between diffuse (DF) and intestinal (IT) GC remain incompletely characterized, particularly at the transcriptional regulatory level. In the present study, gene regulatory networks were constructed using the Passing Attributes between Networks for Data Assimilation (PANDA) algorithm for DF, IT and mixed GC. The results indicated that >85% of transcription factor (TF)-target edges were shared among all three GC subtypes. In TF enrichment analysis, 13 TFs, including nuclear transcription factor Y subunit α (NFYA) and forkhead box L1, were activated in DF GC, whereas 8 TFs, including RELA proto-oncogene and T-cell leukemia homeobox 1 (TLX1), were activated in IT GC. Out of these identified TFs, NFYA [Hazard ratio (HR) (95% confidence interval, CI)=0.560 (0.349, 0.900), P=0.017] and sex determining region Y [HR (95% CI)=0.603 (0.375, 0.969), P=0.037] were identified as independent prognostic factors in DF GC, but not in IT GC, whereas TLX1 [HR (95% CI)=0.547 (0.321, 0.9325), P=0.027] was identified as an independent prognostic factor in IT GC, but not in DF GC. Verification at the cellular level was also performed; interference of NFYA expression using small interfering RNA in MGC803 cells (DF GC-derived cells) markedly inhibited cell growth and colony formation. Similar effects were also detected in SGC-7901 cells (IT GC-derived cells), but to a lesser extent. In conclusion, identified gene regulatory networks differed between distinct GC subtypes, in which the same TFs had different biological effects. Specifically, NFYA was identified as a DF subtype- specific independent prognostic factor in GC.

Distinct subgroup of the Ras family member 3 (DIRAS3) expression impairs metastasis and induces autophagy of gastric cancer cells in mice

PurposeDistinct subgroup of the Ras family member 3 (DIRAS3), also called Aplasia Ras homolog member I, is a tumor suppressor gene that induces autophagy in several cancer cell lines.MethodsThis study analyzed DIRAS3, and markers of autophagy (p62, and LC3B-II) in surgically resected GC samples from 420 patients. The promotion of autophagy by DIRAS3 in gastric cancer (GC) cells was explored, which might explain its inhibitory role in gastric cancer cells.ResultsDIRAS3 expression in GC was positively correlated with LC3B-II amount, and negatively with metastasis; DIRAS3 and p62 levels were independent prognostic factors in GC. Overexpression of DIRAS3 in BGC-823 cells induced autophagy, led to decreased proliferation, cell cycle arrest in G0/G1 phase, increased apoptosis, and impaired migration and invasion. While knockdown of DIRAS3 promoted proliferation and migration in MKN-45 cells. Overexpression of DIRAS3 in BGC-823 cells elevated autophagy levels in subcutaneous xenograft and inhibited tumor growth in mice; the hematogenous liver and lung metastasis of cancer cells were also suppressed.ConclusionsIn conclusion, the results suggest DIRAS3 may play a role in affecting proliferation and metastatic potential of GC cells, which may be associated with its involvement in autophagy regulation.

Expression and clinical significance of autophagic protein LC3B and EMT markers in gastric cancer.

Background and aimGastric cancer (GC) is a fatal malignancy with high rate of recurrence and metastasis. Here, we investigated the correlations between the expression of autophagic protein LC3B and 2 epithelial–mesenchymal transition-related proteins (E-cadherin and Vimentin) and the clinicopathological factors and prognosis of patients with GC.Materials and methodsThe expression of LC3B, E-cadherin, and Vimentin in GC samples (110 cases) and paracarcinoma tissues (40 cases) was analyzed using the Oncomine databases and further detected by immunohistochemistry. The correlations among these markers expression and clinicopathological features in GC were analyzed. The patients were followed for survival analysis.ResultsCompared to the nontumor tissues, the expression of LC3B and Vimentin proteins were significantly elevated in GC tissues, but the E-cadherin expression was decreased (all p<0.05). Interestingly, LCB expression was positively correlated with Vimentin (r=0.320, p=0.001) and negatively associated with E-cadherin expression (r= −0.484, p<0.001) in GC. The expression of these markers was closely related to tumor differentiation, T classification, TNM stage, and lymph node metastasis (all p<0.05). Furthermore, survival analyses and screening Kaplan–Meier plotter database revealed that GC patients with high LC3B and Vimentin expression levels had a poorer clinical outcome than those with low expression. Conversely, high E-cadherin expression was linked with favorable overall survival (all p<0.05, log-rank test). Multivariate survival analysis demonstrated that LC3B, E-cadherin, and Vimentin expression were independent prognostic factors of GC patients.ConclusionLC3B, E-cadherin, and Vimentin may play an important role in the tumorigenesis of GC, and these marker expressions may serve as additional prognostic indicators for overall survival of patients. The interactions of autophagy and epithelial–mesenchymal transition in GC merits further investigation.

Preoperative apolipoprotein B/apolipoprotein A1 ratio: a novel prognostic factor for gastric cancer.

BackgroundThe correlations between lipid profile (lipid molecules and their derivative indexes) and clinical outcome have been widely testified in many carcinomas, but its prognostic value remains unknown in gastric cancer (GC). Our purpose in the study was to comprehensively evaluate the clinical significance of lipid profile in GC.MethodsWe retrospectively collected clinical information of 1,201 GC patients who received surgery at Sun Yat-sen University Cancer Center from 2005 to 2010. Kaplan–Meier analysis and Cox proportional hazards regression model were performed to determine its prognostic significance.ResultsLipid profile including cholesterol, triglyceride, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), LDL-C/HDL-C ratio, and ApoB/ApoA1 ratio were analyzed. For the first time, we found ApoB/ApoA1 ratio showed the biggest prognostic potency among all lipid-related variables and could act as an independent prognostic factor in GC. Patients with a high ApoB/ApoA1 ratio (≥1) had a shorter overall survival (hazard ratio: 1.373, 95% confidence interval: 1.123–1.68; P=0.002).ConclusionPreoperative serum ApoB/ApoA1 ratio might be used as a novel prognostic indicator of GC.

Combination of CRP and NLR: a better predictor of postoperative survival in patients with gastric cancer.

ObjectivesC-reactive protein (CRP) and neutrophil to lymphocyte ratio (NLR) were independent predictive factors for gastric cancer (GC). Our study was designed to prove the prognostic value of the combination of CRP and NLR (COC-NLR) in GC patients.Materials and methodsA total of 1,058 GC patients who underwent D2 resection from Sun Yat-Sen University Cancer Center between 2003 and 2013 were included. They were divided into three groups (low: NLR ≤2.5, CRP ≤6.1; medium: NLR >2.5, CRP ≤4.5; high: NLR >2.5, CRP >4.5 or NLR ≤2.5, CRP >6.1) by the random forest method. Survival analysis stratified by COC-NLR groups was performed.ResultsThe mean survival time for each group was: for the low group 75.44 months (95% CI: 72.48–78.40), the medium group 56.50 months (95% CI: 50.68–62.31), and the high group 38.65 months (95% CI: 34.51–42.97). The low group showed obviously better overall survival (OS) than other two groups (p<0.001). Survival analysis showed that COC-NLR had statistical significance in both univariate and multivariate analyses (p<0.01).ConclusionThis study showed that COC-NLR could work as an independent prognostic factor in GC and provide more accurate prediction than single NLR or CRP.

Clinical prognostic value of A FOXM1 related long non-coding RNA expression in gastric cancer.

The aim of this study was to explore FOXM1-related LncRNA 1(FRLnc1) expression level in gastric cancer (GC) and demonstrate its association with the prognosis. A total of 173 GC patients from Affiliated Hospital of Jining Medical University were enrolled in the study. GC tissue samples were quantified for FRLnc1 expression level using quantitative PCR (qPCR) method. The relevance between FRLnc1 expression and clinicopathological features was determined by x2-test. The association between FRLnc1 expression and overall survival was estimated by the Kaplan-Meier method. Multivariate and univariate analysis were performed to explore whether FRLnc1 was an independent prognostic factor for GC patients. We found that FRLnc1 expression was higher in GC tissues than corresponding adjacent tissues (p < 0.01). Increased FRLnc1 expression was associated with depth of tumor (p = 0.004), differentiation degree (p = 0.032), distant metastasis (p = 0.007), TNM stage (p = 0.006) and lymph node metastasis (p = 0.012). More importantly, Kaplan-Meier survival analysis demonstrated that overall patient survival for those with low FRLnc1 expression was significantly longer than those patients with high FRLnc1 expression (p < 0.001). Multivariate analysis suggested that FRLnc1 expression was an independent prognostic marker for survival in patients with GC. The data presented in this work firstly suggested that FRLnc1 may be a prognostic predictor in GC.

Low FAT4 expression is associated with a poor prognosis in gastric cancer patients.

In this study, we investigated the role of Fat atypical cadherin 4 (FAT4) in gastric cancer (GC) progression. Immunohistochemical analysis showed lower FAT4 expression in tumor tissues from GC patients than in normal gastric epithelium. Lower FAT4 expression was associated with poor prognosis, tumor size and invasion, and lymph node and distant metastases. Multivariate analysis showed that TNM stage, lymph node and distant metastases, Lauren classification, and FAT4 expression were independent prognostic factors in GC. Methylation-specific PCR analysis showed increased FAT4 promoter methylation in GC tumor tissues and cell lines. Higher FAT4 promoter methylation was associated with low FAT4 expression and a poor prognosis. BGC-823 cells showed increased FAT4 expression upon treatment with 5-azacytidine, demethylating agent. FAT4 knockdown in BGC-823 cells led to increased cell proliferation, migration and invasiveness. Moreover, xenografts of BGC-823 cells with FAT4 knockdown showed enhanced tumor growth and metastasis in nude mice. These findings demonstrate that low FAT4 expression is associated with a poor prognosis in GC patients.

Downregulation of tissue miR-338-3p predicts unfavorable prognosis of gastric cancer.

Numerous studies have proved that microRNAs (miRNAs) play crucial roles in the tumorigenesis and progression of gastric cancer (GC). Our study was to investigate the correlation between miR-338-3p expression and clinical features as well as prognosis of GC. A total of 138 GC tissue specimens and adjacent non-cancerous tissues were collected for further analysis, then quantitative PCR method was used to detect the relative miR-338-3p expression. Our study showed that tissue miR-338-3p level was greatly decreased in cancer tissues compared with paired normal tissues. Furthermore, loss of tissue miR-338-3p was positively associated with aggressive clinical characteristics (advanced clinical stage, poorer differentiation and lymph node invasion), shorter overall survival and recurrence free survival. Finally, tissue miR-338-3p expression was confirmed to be an independent prognostic factor for GC. Overall, our findings indicate that miR-338-3p acts as a tumor suppressor in GC and tissue miR-338-3p might serve as a novel prognostic biomarker of GC.

Long noncoding RNA FEZF1-AS1 indicates a poor prognosis of gastric cancer and promotes tumorigenesis via activation of Wnt signaling pathway

Long non-coding RNAs (lncRNAs) have been demonstrated that it plays very important role in development and progression of carcinomas. LncRNA FEZF1 antisense RNA 1 (FEZF1-AS1) has been proved to be implicated in tumor initiation and progression of various cancers, recently. Nevertheless, the biological function and clinical significance of lncRNA FEZF1-AS1 in gastric cancer (GC) are not clear enough. Here, we concentrated on the association of FEZF1-AS1 expression and clinicopathological factors in GC tissues and cells. Moreover, we explored the potential regulatory mechanisms. The results showed that lncRNA FEZF1-AS1 was observably upregulated in human GC tissues and GC cell lines, compared with the adjacent non-tumor tissues and human gastric epithelial cell line (GES-1). Moreover, high expression of lncRNA FEZF1-AS1 was significantly associated with later stage and higher grade. Furthermore, Kaplan-Meier survival analysis was conducted, indicating that lncRNA FEZF1-AS1 may be an independent prognostic factor in GC. Additionally, the area under the receiver operating characteristic (ROC) curve of lncRNA FEZF1-AS1 exhibited its diagnostic value in GC. Notably, whenever the lncRNA FEZF1-AS1 was silenced, the proliferation of GC cells were significantly inhibited and the cell cycle was arrested at a G0/G1 stage in GC cells. Furthermore, downregulation of lncRNA FEZF1-AS1 could suppress the activation of the Wnt/β-catenin signaling pathway. Conclusively, our findings indicated that lncRNA FEZF1-AS1 could be considered as a novel biomarker for the treatment of GC.

Serum metabolomic profiling of human gastric cancer and its relationship with the prognosis.

ObjectiveThis study was aimed to investigate serum metabolites in gastric cancer (GC) patients and their relationships with the prognosis of GC in order to find potential specific serum biomarkers for GC.MethodsBlood samples of 125 GC patients of unifocal GC at initial stage and 38 healthy people recruited in our hospital from September 2008 to August 2009 were analyzed by using high performance liquid chromatography coupled with electrospray ionization/quadrupole-time-of-flight mass spectrometry (HPLCESI/Q-TOFMS). Multiple statistical methods like principal component analysis (PCA), hierarchical clustering analysis, partial least squares discriminant analysis (PLS-DA), multivariate COX regression analysis, variance analysis and K-M survival curve were applied to analyze the raw obtained mass data in order to analyze the independent prognostic factors of GC. The structures of these metabolites were confirmed by comparing the m/z ratio and ion mode of with the data published from HMDB (www.hmdb.ca) databases.ResultsBy PLS-DA test, 16 serum metabolites in ESI+ mode of VIP>1 in both test group and validation group could definitely distinguish GC patients from healthy peoples (p<0.05). Multivariate COX regression analysis showed TNM staging, 2,4-hexadienoic acid, 4-methylphenyl dodecanoate and glycerol tributanoate were independent prognostic factors of GC (p<0.05). In the K-M survival analysis, the survival rate in high level group of the 3 selected serum metabolites together or alone was significant lower than in those in low level group (p<0.05).ConclusionLow serum levels of 2,4-hexadienoic acid, 4-methylphenyl dodecanoate and glycerol tributanoate may be important independent prognostic factors of GC.

Correlations of Hemoglobin Level and Perioperative Blood Transfusion with the Prognosis of Gastric Cancer: A Retrospective Study.

BackgroundThis study was designed to explore the correlations of hemoglobin level (Hb) and perioperative blood transfusion with the prognosis of gastric cancer (GC).Material/MethodsOur study consisted of 210 patients with GC who all received a D2 radical operation. These patients were assigned into three groups: 68 cases in group A (blood transfusion >5 U); 59 cases in group B (blood transfusion <5 U); 83 cases in group C (without blood transfusion). A 5-year follow-up was conducted to evaluate the disease-free survival of the patients. Univariate analysis was performed to reveal the relationship between the indicators and the patients with GC. Kaplan-Meier method was employed to analyze the survival rate of patients, and Cox regression analysis was applied to determine the independent prognostic factors of GC.ResultsThe univariate analysis indicated that age, perioperative blood transfusion amount, TNM staging, maximal tumor diameter, differentiation degree and invasion degree were associated with the prognosis of GC. The Kaplan-Meier curve showed that the disease-free survival rate was declined in the patients who were older, those received more amount of blood transfusion, those in advanced TNM staging, those had larger tumor diameter, and those with decreased degree of differentiation and invasion. Cox regression analysis indicated that perioperative blood transfusion, maximal tumor diameter and invasion degree were the independent factors affecting disease-free survival of the GC.ConclusionsOur study revealed that large amount of perioperative blood transfusion leads to poor prognosis of GC.

Clinical significance and prognostic value of Triosephosphate isomerase expression in gastric cancer.

Triosephosphate isomerase (TPI) is highly expressed in many human cancers and is involved in migration and invasion of cancer cells. However, TPI clinicopathological significance and prognostic value in gastric cancer (GC) are not yet well defined. The aim of the present work was to evaluate TPI expression in GC tissue and its prognostic value in GC patients.TPI expression was analyzed in 92 primary GC tissues and 80 adjacent normal mucosa tissues from GC patients undergoing gastrectomy by immunohistochemical analysis of tissue microarrays (TMAs). Univariate and multivariate analyses were performed to investigate TPI prognostic significance in GC patients.Immunohistochemical staining score showed that TPI expression in cancer tissues was significantly higher than in adjacent normal mucosa (P < .001). Univariate analysis revealed that TPI expression, depth of invasion, lympho node metastasis, tumor node metastasis (TNM) stage, and tumor diameter were associated with negative prognostic predictors for overall survival in GC patients (P < .05). High TPI expression represented a significant predictor of shorter survival in GC patients with positive lymphatic metastasis (P = .022) and tumor diameter >5 cm (P = .018). Cox multivariate analysis identified TPI expression, TNM stage, and tumor diameter as independent prognostic factors in GC patients.TPI expression might be considered as a novel prognostic factor to evaluate GC patients’ survival.

Preoperative lymphocyte-to-monocyte ratio as a strong predictor of survival and recurrence for gastric cancer after radical-intent surgery.

ObjectivesTo evaluate the predictive value of the preoperative lymphocyte-to-monocyte ratio (LMR) for the prognosis of patients with gastric cancer (GC) after radical-intent surgery.MethodsWe retrospectively analyzed 1,810 patients who underwent radical-intent gastrectomy for primary GC from December 2008 to December 2013. X-tile software was used to identify the optimal value for blood LMR. Nomograms were developed to predict overall survival (OS) and recurrence-free survival (RFS) after surgery.ResultsLMR was significantly lower in patients with GC than in matched normal volunteers (P<0.001). As shown by forest plots, the long-term outcomes were poorer in the low LMR group than in the high LMR group when considering subgroups separated by clinical characteristics. Cox regression analysis showed that LMR was an independent prognostic factor for OS (P<0.001) and RFS (P=0.001). Nomograms, combining LMR with age, T stage, and N stage, showed better discriminative abilities than the AJCC staging system did in predicting 5-year survival and recurrence from the time of surgery. The recurrence rate was 30.4% (550/1810) and was significantly higher in the low LMR group than in the high LMR group (P<0.05). The LMR was also closely correlated with liver and lymph node metastases (both P<0.05).ConclusionAs an independent prognostic factor for GC, preoperative LMR can improve the predictability of individual survival and recurrence. Furthermore, because liver and lymph node metastases were more commonly observed in patients with low blood LMR before surgery, these patients should be closely followed after the operation.

Clinical Significance of Serum p53 Antibody in the Early Detection and Poor Prognosis of Gastric Cancer.

The aim of this retrospective study was to evaluate the clinical relevance of serum p53 antibody (S-p53Ab) as a biomarker and to investigate whether its diagnostic value could be improved when combined with other biomarkers of gastric cancer (GC). Serum samples were obtained preoperatively from 208 patients with histologically-confirmed GC, including 126 stage I patients (60.6%). Levels of S-p53Ab were assessed by a commercial laboratory using an anti-p53 detection kit. The cut-off value for S-p53Ab was 1.3 U/ml. S-p53Ab was detected in 16.3% (34 of 208) of patients with GC, including 13.6% (22 of 162) of patients with early-stage GC. The positive rates for S-p53Ab, carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA) of patients with stage I GC were 10.3% (13/126), 2.4% (3/126), and 8.7% (11/126), respectively. Positivity for S-p53Ab was not associated with CA19-9 or CEA positivity (p=0.098 and 0.053, respectively). The positive rate for a diagnosis of GC increased from 16.3% to 29.3% when S-p53-Ab was combined with CEA in this study. We found no significant correlation between the presence of S-p53Ab in GC and overall survival. Conversely, Cox regression analysis revealed that a high level of CA19-9 was an independent prognostic factor for GC in this series (hazard ratio(HR)=3.864; 95% confidence interval(CI)= 1.248-11.959; p=0.019). Kaplan-Meier analyses demonstrated significant differences in survival between patients with elevated levels of both S-p53Ab and CEA and those with elevated levels of only one or neither. The diagnostic rate of S-p53Ab was better than that of CA19-9 and CEA in patients with stage I GC. Combined detection of S-p53Ab and CEA may improve the diagnostic sensitivity and may permit more accurate stratification of GC patients.

Overexpression of stromal interaction molecule 1 may promote epithelial‑mesenchymal transition and indicate poor prognosis in gastric cancer.

The aim of the present study was to investigate the prognostic significance of stromal interaction molecule 1 (STIM1) expression in gastric cancer (GC) and examine the association between STIM1 and epithelial-mesenchymal transition (EMT). Immunohistochemical staining was performed to detect STIM1, E-cadherin, β-catenin and matrix metalloproteinase-9 (MMP-9) in 170 GC and 35 adjacent healthy gastric tissue samples. Positive staining of STIM1, E-cadherin, β-catenin and MMP-9 in GC tissues was significantly greater compared with adjacent healthy tissues (P<0.05). Clinicopathological analysis revealed that STIM1 expression was significantly associated with LNM (P<0.001) and tumor-node-metastasis stage (P=0.01). The overall survival rate was significantly reduced in STIM1-positive compared with STIM1-negative patients (P=0.043). Cox regression analysis indicated that STIM1 expression and LNM were independent prognostic factors for GC. Chi-square tests suggested that STIM1 expression in GC tissues was significantly associated with E-cadherin (P<0.001) and β-catenin (P<0.001), whereas no association was observed between STIM1 and MMP-9 expression (P>0.05). In conclusion, the results of the present study suggested that STIM1 may be a valuable prognostic marker in GC patients, and that STIM1 may increase GC motility and invasiveness by promoting epithelial-mesenchymal transition.

ITGBL1 Predicts a Poor Prognosis and Correlates EMT Phenotype in Gastric Cancer.

Integrin, beta-like 1 (ITGBL1), a β-integrin-related extracellular matrix protein, was found more commonly up-regulated in gastric cancer (GC) by screening and analyzing Gene Expression Omnibus (GEO) and Oncomine databases, reminding us to explore its prognostic significance in GC. In our current study, we observed that ITGBL1 expression was significantly up-regulated in GC compared with normal controls in clinical specimens. In addition, elevated ITGBL1 expression was positively correlated with patients' tumor-node-metastasis (TNM) stage and distant metastasis. Kaplan-Meier analysis indicated that high ITGBL1 expression was significantly associated with shorter survival times in GC patients. Multivariate Cox regression analysis confirmed ITGBL1 expression as an independent prognostic factor in GC. Gene set enrichment analysis (GSEA) of multiple GEO datasets revealed a close relationship between ITGBL1 expression and the KRAS/epithelial-mesenchymal transition (EMT) signaling pathway. In conclusion, these data provide evidences that ITGBL1 is a potential predictor and may be involved in cancer cell invasion and metastasis via inducing EMT, and the ITGBL1-related pathways may represent a novel therapeutic strategy for treatment of GC.

Expression of CRM1 and CDK5 shows high prognostic accuracy for gastric cancer.

AIMTo evaluate the predictive value of the expression of chromosomal maintenance (CRM)1 and cyclin-dependent kinase (CDK)5 in gastric cancer (GC) patients after gastrectomy.METHODSA total of 240 GC patients who received standard gastrectomy were enrolled in the study. The expression level of CRM1 and CDK5 was detected by immunohistochemistry. The correlations between CRM1 and CDK5 expression and clinicopathological factors were explored. Univariate and multivariate survival analyses were used to identify prognostic factors for GC. Receiver operating characteristic analysis was used to compare the accuracy of the prediction of clinical outcome by the parameters.RESULTSThe expression of CRM1 was significantly related to size of primary tumor (P = 0.005), Borrmann type (P = 0.006), degree of differentiation (P = 0.004), depth of invasion (P = 0.008), lymph node metastasis (P = 0.013), TNM stage (P = 0.002) and distant metastasis (P = 0.015). The expression of CDK5 was significantly related to sex (P = 0.048) and Lauren’s classification (P = 0.011). Multivariate Cox regression analysis identified that CRM1 and CDK5 co-expression status was an independent prognostic factor for overall survival (OS) of patients with GC. Integration of CRM1 and CDK5 expression could provide additional prognostic value for OS compared with CRM1 or CDK5 expression alone (P = 0.001).CONCLUSIONCRM1 and CDK5 co-expression was an independent prognostic factors for GC. Combined CRM1 and CDK5 expression could provide a prognostic model for OS of GC.

Tspan5 is an independent favourable prognostic factor and suppresses tumour growth in gastric cancer.

Tetraspanins are believed to interact with specific partner proteins forming tetraspanin-enriched microdomains and regulate some aspects of partner protein functions. However, the role of Tspan5 during pathological processes, particularly in cancer biology, remains unknown. Here we report that Tspan5 is significantly downregulated in gastric cancer (GC) and closely associated with clinicopathological features including tumour size and TNM stage. The expression of Tspan5 is inversely correlated with patient overall survival and is an independent prognostic factor in GC. Upregulation of Tspan5 in tumour cells results in inhibition of cell proliferation and colony formation in vitro and suppression of xenograft growth of GC by reducing tumour cell proliferation in vivo. Thus, Tspan5 functions as a tumour suppressor in stomach to control the tumour growth. Mechanistically, Tspan5 inhibits the cell cycle transition from G1-S phase by increasing the expression of p27 and p15 and decreasing the expression of cyclin D1, CDK4, pRB and E2F1. The correlation of Tspan5 expression with the expression of p27, p15, cyclin D1, CDK4, pRB and E2F1 in vivo are also revealed in xenografted tumours. Reconstitution of either cyclin D1 or CDK4 in Tspan5-overexpressing GC cells rescues the inhibitory phenotype produced by Tspan5, suggesting that cyclin D1/CDK4 play a dominant role in mediating the suppression of tumour growth by Tspan5 in GC. Our results suggest that Tspan5 may serve as a prognostic biomarker for predicting outcome of GC patients and provide new insights into the pathogenesis of GC and rational for the development of clinical intervention strategies against GC.

Expression of hypoxia-inducible factor 1α in gastric cancer and its clinical signficance

To explore the expression level and location of hypoxia-inducible factor 1α (HIF-1α) in gastric cancer (GC) tissues and their relationship with clinicopathological features and clinical outcomes. From July to September 2015, 27 pairs of fresh paired GC tissues and adjacent normal tissues were gathered from the Eighth Department of General Surgery of the First Affiliated Hospital of Anhui Medical University. Quantitative real-time PCR (qRT-PCR) and Western blot were performed to detect the expression of HIF-1α mRNA and protein in these tissues. A total of 191 GC tissues and 46 randomly selected adjacent normal gastric tissues were consecutively collected between December 2006 and September 2008 from Department of General Surgery of the same hospital. Immunohistochemistry were performed on them to detect the expression of HIF-1α and CD34[described in terms of microvessel density (MVD)], and correlation of different locations of HIF-1α (in cytoplasm or nucleus) with MVD, clinicopathological features, and clinical prognosis was analyzed. The average relative expression level of HIF-1α mRNA in GC tissues (0.625±0.170) was significantly higher than in normal adjacent tissues (0.218±0.036, t=2.336, P=0.023) by qRT-PCR. From the results of Western blot, the expression level of HIF-1α protein increased in GC tissues compared with its corresponding normal tissues. Immunohistochemistry results revealed that positive HIF-1α staining was observed in 67.54% GC tissues and 45.65% normal tissues, with significant difference (P=0.006). And 35.08% in GC and 45.65% in normal tissues were cytoplasmic positive (P=0.138); while 37.17% in GC and only 2.17% in normal tissues were nuclear positive, with significant difference (P<0.001). High differentiation group and TNM clinical early stage (Ⅰ+ Ⅱ) group had significantly higher cytoplasmic HIF-1α expression positive rate compared with low differentiation group (P=0.008) and TNM clinical intermediate-advanced stage (Ⅲ+ Ⅳ) group (P=0.019); whereas low differentiation group had significantly higher nuclear HIF-1α expression positive rate compared with high differentiation group (P=0.043). The mean MVD in the nuclear HIF-1α positive GC group (115.6 ± 7.8) was higher than that in the cytoplasmic HIF-1α positive GC group (93.1±7.5, t=2.077, P=0.040). The median follow-up time was 56(3-81)months. Kaplan-Meier survival analysis and Log-Rank test results showed that nuclear HIF-1α positive patients had a shorter survival time (median 45 months) than cytoplasmic HIF-1α positive patients (median 64 months, P<0.001). Multivariate Cox regression analysis revealed that differentiation (HR=1.713; 95% CI: 1.019-2.882), depth of invasion (tumor stage, HR=6.137; 95% CI: 1.832-20.556) and lymph node metastasis (HR=2.788; 95% CI: 1.313-5.920) were independent prognostic factors for GC (all P<0.05). Different location of HIF-1α protein may be realted to the tumorigenesis and progression of GC, and may become a potential prognostic indicator of GC.