Expression In Gastric Carcinoma Research Articles

Prognostic Value and Clinical Pathology of MACC-1 and c-MET Expression in Gastric Carcinoma

This study was to assess the expression of MACC-1 and c-MET in gastric cancer, and to correlate this expression with clinicohistological parameters and patient prognosis. Total RNA was extracted from cancer tissue and adjacent normal mucosa from frozen biopsy specimens of 30 patients with gastric cancer, and MACC-1 expression was assessed by RT-PCR. MACC-1 and c-MET protein expression were also assessed in paraffin-embedded tissues obtained from 436 tumor mucosa and 92 normal mucosa specimens by immunohistochemistry. The correlation between MACC-1 and c-MET expression and clinicopathological factors (age, sex, histology, tumor depth, lymph node status and vessel invasion) were also evaluated. RT-PCR analysis revealed that MACC-1 expression was significantly higher in cancerous mucosa compared with normal tissue. Immunohistochemical analysis indicated that MACC-1 and c-MET were moderately or strongly expressed in gastric cancer tissue, whereas expression was weak or absent in non-cancer tissue. Expression of MACC-1 or c-MET was significantly associated with larger tumor size, deeper tumor invasion, presence of lymph node metastasis, lymphatic involvement, venous invasion, distant metastasis and advanced clinical stage. However, only MACC-1 exhibited significantly greater expression in carcinomas from the higher age group. The intensity of MACC-1 and c-MET expression was also positively correlated. Survival analysis of the 436 gastric cancer patients revealed that patients in clinical stages I, II and III exhibiting lower MACC-1 and c-MET expression had a higher 5-year survival rate compared with patients expressing high levels of these proteins. Multivariate analysis revealed that MACC-1 and c-MET may be independent prognostic indexes of gastric carcinoma (P < 0.01). Our findings confirm that MACC-1 and c-MET expression is strongly related to gastric cancer stage and degree of malignancy, and is inversely correlated to patient prognosis. Thus, MACC-1 and c-MET may interact to promote tumorigenesis and their expression may be used as independent prognostic markers in gastric cancer.

Up-regulation of Ago2 expression in gastric carcinoma

Argonaute (Ago) proteins have been demonstrated to be widely expressed and involved in post-transcriptional gene silencing and thus play key roles in carcinogenesis. Nevertheless, little is known about the specific role of Ago2 in gastric cancer (GC). Thus, we aimed to study the expression of Ago2 in 363 primary GC, 8 corresponding lymph node metastases and 10 non-neoplastic surrounding gastric epithelium tissues by immunohistochemical analyses and tissue microarray. The expression of Ago2 was also correlated with clinicopathological characteristics and HER-2 status. Ago2 expression levels in primary GC and corresponding lymph node metastases were significantly higher compared with healthy controls (P < 0.05). But, there was no difference of Ago2 between GC and its metastatic lymph node (P > 0.05). Ago2 up-regulation had no correlation with GC patients' age, tumor location, tumor size, gross morphology or tumor infiltration. However, we found that Ago2 was different between HER-2 positive and HER-2 negative groups (P = 0.044), which had been demonstrated to be related to GC prognosis. And there was a great correlation between Ago2 expression and the tumor differentiation (P = 0.007), lymph node invasion (P = 0.000) and clinical stage (P = 0.006). Interestingly, Ago2 was also correlated to patients' gender (P = 0.004), which may suggest a possible role of hormonal signal in the mechanisms of Ago2. Thus, our results suggested that up-regulation of Ago2 may play an important role in GC carcinogenesis and progression. Further studies on the cellular functions of Ago2 need to address these issues.

Reduced expression of Rho GDP dissociation inhibitor 2 mRNA is associated with lymph node metastasis in gastric carcinoma

Small GTPase proteins, including RhoA, RhoB, RhoC, Rac1 and cdc42, are molecules that have significant roles in linking cell shape and cell cycle progression in cytoskeletal arrangements and mitogenic signaling. Rho GDP dissociation inhibitor 2 (RhoGDI2) has recently been identified as a metastasis suppressor gene in models of bladder cancer. RhoGDI2 has also been identified as a potential regulator of tumorigenesis and cancer progression. The present study aimed to clarify the significance of RhoGDI2 gene expression in gastric carcinoma and to evaluate the outcome of affected patients. A total of 46 pairs of normal mucosa and cancer specimens were obtained from patients who had undergone a gastrectomy for primary gastric carcinoma and were subjected to semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) for RhoGDI2. The expression of RhoGDI2 mRNA was significantly higher in early-stage gastric cancer specimens compared with the normal gastric epithelium samples. By contrast, the depth of the tumor was negatively correlated with RhoGDI2 mRNA expression. In addition, a reduced expression of RhoGDI2 mRNA was associated with venous system invasion and lymph node metastasis. RhoGDI2 mRNA was more frequently expressed in differentiated adenocarcinoma compared with poorly-differentiated adenocarcinoma. Although the statistical significance was not established, RhoGDI2-positive patients tended to have a superior oncological outcome compared with RhoGDI2-negative patients. The reduced expression of RhoGDI2 mRNA in gastric carcinoma is associated with venous system invasion and lymph node metastasis.

Differences in Gastric Carcinoma Microenvironment Stratify According to EBV Infection Intensity: Implications for Possible Immune Adjuvant Therapy

Epstein-Barr virus (EBV) is associated with roughly 10% of gastric carcinomas worldwide (EBVaGC). Although previous investigations provide a strong link between EBV and gastric carcinomas, these studies were performed using selected EBV gene probes. Using a cohort of gastric carcinoma RNA-seq data sets from The Cancer Genome Atlas (TCGA), we performed a quantitative and global assessment of EBV gene expression in gastric carcinomas and assessed EBV associated cellular pathway alterations. EBV transcripts were detected in 17% of samples but these samples varied significantly in EBV coverage depth. In four samples with the highest EBV coverage (hiEBVaGC – high EBV associated gastric carcinoma), transcripts from the BamHI A region comprised the majority of EBV reads. Expression of LMP2, and to a lesser extent, LMP1 were also observed as was evidence of abortive lytic replication. Analysis of cellular gene expression indicated significant immune cell infiltration and a predominant IFNG response in samples expressing high levels of EBV transcripts relative to samples expressing low or no EBV transcripts. Despite the apparent immune cell infiltration, high levels of the cytotoxic T-cell (CTL) and natural killer (NK) cell inhibitor, IDO1, was observed in the hiEBVaGCs samples suggesting an active tolerance inducing pathway in this subgroup. These results were confirmed in a separate cohort of 21 Vietnamese gastric carcinoma samples using qRT-PCR and on tissue samples using in situ hybridization and immunohistochemistry. Lastly, a panel of tumor suppressors and candidate oncogenes were expressed at lower levels in hiEBVaGC versus EBV-low and EBV-negative gastric cancers suggesting the direct regulation of tumor pathways by EBV.

S100 calcium-binding protein A4 is a novel independent prognostic factor for the poor prognosis of gastric carcinomas

Overexpression of the S100 calcium-binding protein A4 (S100A4) is involved in epithelial-to-mesenchymal transition, oncogenic transformation, angiogenesis, cytoskeletal integrity and cancer metastasis. Here, we elucidated the role of S100A4 in tumorigenesis and progression of gastric carcinomas. S100A4 expression in gastric carcinomas, adenomas and adjacent non-neoplastic mucosa was analyzed by immunohistochemical, real-time reverse transcriptase (RT)-polymerase chain reaction (PCR) and western blot analyses, and was correlated with various clinicopathological parameters. S100A4 protein expression was increased gradually in the following order: gastritis (19.2%), intestinal metaplasia (IM; 23.3%), dysplasia (34.9%) and carcinoma (55.2%; P<0.001). S100A4 was positively correlated with tumor size, depth of invasion, lymphatic invasion, lymph node metastasis and tumor-node-metastasis (TNM) staging (P<0.05), but not with the age and gender of the carcinoma patients (P>0.05). Intestinal-type (IT) carcinomas showed a higher S100A4 expression than diffuse-type (DT) carcinomas (P<0.001). S100A4 mRNA expression also increased in the following order: gastritis < IM < dysplasia < carcinoma (P<0.05). S100A4 overexpression was observed in gastric carcinomas with a larger diameter, deeper invasion, lymph node metastasis and in IT carcinoma (P<0.05). Univariate analysis using the Kaplan-Meier method indicated a lower cumulative survival rate for patients with weak or moderate S100A4 expression compared with patients not expressing S100A4 (P<0.001). Multivariate analysis using Cox's proportional hazard model demonstrated that depth of invasion, lymphatic or venous invasion, lymph node metastasis, TNM staging and S100A4 expression were independent factors for poor patient prognosis (P<0.05). In conclusion, S100A4 upregulation is positively associated with the pathogenesis, growth, invasion, metastasis and differentiation of gastric carcinomas. S100A4 may be a promising marker indicative of the aggressive behavior and prognosis of gastric carcinomas.

Clinicopathologic Significance of Putative Stem Cell Marker, CD44 and CD133, in Human Gastric Carcinoma

CD44 and CD133 have been reported as putative stem cell markers. However, the clinicopathologic significance of CD44 and CD133 expression in patients with gastric carcinoma (GC) has not been clearly elucidated. Immunohistochemistry (IHC) was performed to investigate the CD44 and CD133 expression in gastric carcinomas and normal mucosal tissues. Receiver operating characteristic (ROC) curve analysis, spearman's rank correlation, Kaplan-Meier plots, and Cox proportional hazards regression model were used to analyze the data. The highly expressed CD44 and CD133 were observed in 27/152 (17.7%) and 64/152 (42.1%) of GCs and in 4/60 (6.7%) and 15/60 (25.0%) normal gastric mucosal tissues, respectively (P < 0.05, Fisher's exact test). High expression of CD44 was significantly correlated with tumor poorer differentiation, presence of distant metastasis, advanced TNM stage, and tumor relapse; and high expression of CD133 was positively associated with tumor invasion depth, presence of distant metastasis and advanced TNM stage. More importantly, high-expressed CD44 and CD133 were both associated with shorter survival as evidenced by univariate and multivariate analysis. Our study introduces high expression of CD44 and CD133 as adverse independent prognostic factors in GC patients. The combined CD44 and CD133 expression may become a useful tool for identifying patients with different clinical outcomes.

MK-1 Expression in Gastric Carcinoma with Liver Metastasis

The prognosis for gastric carcinoma patients with liver metastasis is very poor. This retrospective study investigated the prognostic significance of MK-1 expression in gastric carcinoma patients with liver metastasis. Immunohistochemical staining using monoclonal antibody FU-MK-1 against MK-1 antigen was performed on paraffin-embedded tissues from 64 gastric carcinoma patients with liver metastasis. We attempted to determine the presence of any relationship between pathological prognostic factors and the expression of MK-1 in 64 gastric carcinoma patients with liver metastasis. MK-1 expression was found in 43 (67%) of 64 tumor samples. MK-1 expression was significantly higher in the intestinal type (73%) than in the diffuse type carcinoma (33%, P = 0.049). Multivariate analysis showed that MK-1 expression and lymph node metastasis were significant factors for overall survival. The difference between overall survival rates with positive or negative MK-1 expression was statistically significant as shown by Kaplan-Meier survival analysis (P < 0.0001; log-rank). In addition, the difference between cumulative disease-free survival rates with positive or negative MK-1 expression in gastric carcinoma patients with metachronous liver metastasis was statistically significant as well, as shown by Kaplan-Meier survival analysis (P = 0.0006; log-rank). The prognostic significance of MK-1 expression as a biological tumor marker was demonstrated in a series of gastric carcinoma patients with liver metastasis. MK-1 positivity may be a reliable marker for predicting and taking measures to control liver metastasis after curative gastrectomy for gastric carcinoma.

Clinicopathological correlation and prognostic significance of protein kinase cα overexpression in human gastric carcinoma.

ObjectivesThis study investigated the PKCα protein expression in gastric carcinoma, and correlated it with clinicopathological parameters. The prognostic significance of PKCα protein expression in gastric carcinoma was analyzed.MethodsQuantitative real-time PCR test was applied to compare the PKCα mRNA expression in tumorous and nontumorous tissues of gastric carcinoma in ten randomly selected cases. Then PKCα protein expression was evaluated in 215 cases of gastric carcinoma using immunohistochemical method. The immunoreactivity was scored semiquantitatively as: 0 = absent; 1 = weak; 2 = moderate; and 3 = strong. All cases were further classified into two groups, namely PKCα overexpression group with score 2 or 3, and non-overexpression group with score 0 or 1. The PKCα protein expression was correlated with clinicopathological parameters. Survival analysis was performed to determine the prognostic significance of PKCα protein expression in patients with gastric carcinoma.ResultsPKCα mRNA expression was upregulated in all ten cases of gastric carcinoma via quantitative real-time PCR test. In immunohistochemical study, eighty-eight out of 215 cases (41%) of gastric carcinoma revealed PKCα protein overexpression, which was statistically correlated with age (P = 0.0073), histologic type (P<0.0001), tumor differentiation (P = 0.0110), depth of invasion (P = 0.0003), angiolymphatic invasion (P = 0.0373), pathologic stage (P = 0.0047), and distant metastasis (P = 0.0048). We found no significant difference in overall and disease free survival rates between PKCα overexpression and non-overexpression groups (P = 0.0680 and 0.0587). However, PKCα protein overexpression emerged as a significant independent prognostic factor in multivariate Cox regression analysis (hazard ratio 0.632, P = 0.0415).ConclusionsPKCα protein is upregulated in gastric carcinoma. PKCα protein expression is statistically correlated with age, histologic type, tumor differentiation, depth of invasion, angiolymphatic invasion, pathologic stage, and distant metastasis. The PKCα protein overexpression in patients with gastric carcinoma is a significant independent prognostic factor in multivariate Cox regression analysis.

Clinical significance of Fas, VEGF, and EGFR expression in advanced gastric carcinoma.

58 Background: Researches had proved that apoptotic signal proteins Fas-mediated cellular apoptosis influenced development of gastric carcinoma and affected survival of gastric carcinoma patients. Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) over expression had been associated with poor survival in several cancers including gastric carcinoma. Methods: Immunohisto-chemistry was performed to detect Fas, EGFR and VEGF protein expression in 60 newly diagnosed patients with gastric carcinoma in the First Affiliated Hospital of Sun Yat-sen University from November 1999 to June 2005. Clinical Data of these patients were reviewed. Time to progression (TTP) and overall survival (OS) were compared by log-rank test according to the expression status of Fas, EGFR and VEGF. Results: There were 40 males and 20 females, all patients were stage IV. All patients were treated with infused fluorouracil plus leucovorin and oxaliplatin or paclitaxel. The positive rate of Fas, EGFR and VEGF in gastric carcinoma was 73.3%, 35% and 40% respectively. TTP for patients with Fas positive was significantly superior to patients with Fas-negative (p&lt;0.05). EGFR and VEGF were not correlated with TTP (p&gt;0.05). Fas, EGFR and VEGF were not associated with overall survival(p&gt;0.05). Conclusions: Fas, EGFR and VEGF are often expressed in gastric carcinoma. Fas expression is correlated with longer TTP. EGFR and VEGF expression were not associated with TTP. Fas, EGFR and VEGF were not a prognostic factor for OS.

Adiponectin receptor expression in gastric carcinoma: implications in tumor development and progression

Adiponectin, an adipocyte-secreted endogenous insulin sensitizer, appears to play an important role in progression of several malignancies. Expression of adiponectin receptors--AdipoR1 and AdipoR2--has been documented in gastric cancer (GC) cell lines, but its role in GCs is still controversial. We investigated expression level of 2 adiponectin receptors and correlated their expression with prognosis in GC patients. We immunohistochemically evaluated AdipoR1 and AdipoR2 expression in 59 non-neoplastic gastric mucosas, 48 gastric adenomas, 250 GCs, and 58 lymph nodes involved by metastatic GC and assessed its association with clinicopathologic characteristics. Expression rates of both receptors increased stepwise in non-neoplastic gastric mucosa, gastric adenoma, intestinal-type GC, and metastatic GC (p < 0.001). AdipoR1 and AdipoR2 expression was observed in 85 (34.0 %) and 118 (47.2 %) GC cases, respectively. Expression rates were higher in intestinal-type GC than in diffuse-type GC (p < 0.001 and 0.016, respectively). AdipoR1 and AdipoR2 expression was more frequent in advanced GC than in early GC (p < 0.001, each) and was associated with lymphatic invasion (p = 0.046 and 0.001, respectively). AdipoR2 expression was associated with poor overall and disease-free survival (p = 0.001 and 0.007, respectively). AdipoR1 expression was associated with poor disease-free survival for intestinal-type GC patients (p = 0.046). In multivariate analysis, AdipoR2 was an independent prognostic factor for intestinal-type GC (p = 0.017). Adiponectin receptor expression is related to GC development and progression, especially intestinal-type GC. Thus, adiponectin receptor expression can serve as a prognostic marker in GC patients.

Clinicopathologic significance of miR-10b expression in gastric carcinoma

We have investigated microRNA (miRNA) expression profiles of gastric cancer and the clinicopathologic significance of miR-10b expression in gastric carcinoma. miRCURY LNA Arrays (v.16.0; Exiqon, Vedbaek, Denmark) were used to screen miRNAs in 17 gastric cancers. Reverse transcriptase polymerase chain reaction was performed to determine the expression of miR-10b in 56 gastric tumors. Expression of miR-10b in 436 paraffin-embedded cancer tissues was also investigated. In gastric cancer, 49 miRNAs were overexpressed by 2.0-fold or greater, and 39 miRNAs were down-regulated by 1.5-fold or greater, whereas miR-10b was up-regulated by 2.98-fold. miR-10b was highly expressed in gastric cancer and correlated with size of tumor, Lauren classification, depth of invasion, lymph node and distant metastasis, TNM stage, and prognosis. In stages I, II, and III, the 5-year survival rate of patients with high levels of miR-10b expression was significantly lower than that in patients with low levels of expression. In stage IV, the expression level of miR-10b did not correlate with the 5-year survival rate. miR-10b may play an important role in progression and prognosis of gastric cancer.

Expression and clinical significance of CD73 and hypoxia-inducible factor-1α in gastric carcinoma

To investigate the expression of CD73 and hypoxia-inducible factor-1α (HIF-1α) in human gastric carcinoma, and explore their clinical significance and prognostic value. CD73 and HIF-1α expressions were detected by immunohistochemistry in consecutive sections of tissue samples from 68 gastric carcinoma patients. The peritumor tissues 2 cm away from the tumor were obtained and served as controls. The presence of CD73 and HIF-1α was analyzed by immunohistochemistry using the Envision technique. CD73 and HIF-1α expressions in gastric carcinoma were significantly higher than those in gastric mucosal tissues as control (P < 0.001) and showed a close correlation (Spearman r = 0.390, P = 0.001). Overexpression of CD73 was positively correlated with differentiation of tumor (P = 0.000), histopathology (P = 0.041), depth of invasion (P < 0.001), nodal status (P = 0.003), metastasis (P = 0.013), and the American Joint Committee on Cancer (AJCC) stage (P < 0.001). High expression of HIF-1α was positively correlated with tumor diameter (P = 0.031), depth of invasion (P = 0.022), and AJCC stage (P = 0.035). The overall survival rate was low in the patients with high expression of CD73 (P < 0.001). Moreover, CD73+/HIF-1α+ patients had the worst prognosis (P < 0.001). CD73 expression was proven to be an independent predictor for patients with gastric carcinoma by both multivariate Cox regression analysis (P = 0.021) and receiver operating characteristic curves (P = 0.001). CD73 expression correlates closely with HIF-1α expression in gastric carcinoma. CD73 could be an independent prognostic indicator for gastric carcinoma.

Clinicopathological significance of platelet-derived growth factor B, platelet-derived growth factor recpertor-β, and E-cadherin expression in gastric carcinoma

Aim of the studyPlatelet-derived growth factor B (PDGF-B), a vital growth factor which can induce angiogenesis and epithelial-mesenchymal transition (EMT), is important in the metastasis of many tumors. However, the roles of PDGF-B in gastric carcinoma are largely unknown. We investigated the correlation between PDGF-B, PDGFR-β and E-cadherin expression with the clinical features of gastric carcinoma patients to evaluate the relationship between PDGF-B signaling, E-cadherin and metastasis of gastric carcinoma, the correlation between PDGF-B and E-cadherin expression to assess the roles of PDGF-B signaling in metastasis of gastric carcinoma..Material and methodsWe detected expressions of PDGF-B, PDGFR-β and E-cadherin in gastric carcinoma tissues and normal gastric mucosa tissues of 64 patients with gastric carcinoma who had undergone surgical resection, and investigated their relationships with clinical features and the relationships between PDGF-B and E-cadherin expression in gastric carcinoma.ResultsIn surgical specimens, tumor cells expressed PDGF-B, and PDGFR-β was expressed by tumor stromal cells. E-cadherin was expressed by both tumor cells and normal gastric mucosa cells. Expressions of PDGF-B and PDGFR-β were increased in gastric carcinoma tissues (p < 0.05) and were positively correlated with the depth of cancer invasion, lymph node metastasis and TNM stage (p < 0.05). The expression of E-cadherin was reduced in gastric carcinoma tissues (p < 0.05) and was negatively correlated with the depth of cancer invasion, lymph node metastasis and TNM stage (p < 0.05). The correlation between PDGF-B and E-cadherin expression was negative (p < 0.05).ConclusionOur data indicate that either the overexpression of PDGF-B and PDGFR-β or the underexpression of E-cadherin is correlated with cancer progression and lymphogenous metastasis of gastric carcinoma. The PDGF-B signal pathway might induce EMT by down-regulating expression of E-cadherin to promote metastasis of gastric carcinoma.

Role of altered expression of Nedd4L in the pathogenesis of systemic malignancies

I read with great interest the recent article by Takeuchi et al. (2011) in a recent issue of your journal. The article provides highly interesting reading. Interestingly, the past few years have seen the identification of new evidence that points to a significant role of altered Nedd4L expression in the pathogenesis of several systemic malignancies besides the gallbladder cancers reported in this study. For instance, decreased Nedd4L expression is associated with an increased risk of prostate carcinomas. In fact, higher Gleason scores are seen in prostate carcinomas with attenuated Nedd4L expression Hu et al. 2009. Similarly, decreased Nedd4L expression in gastric carcinomas correlates with a poor prognosis given the augmentation in metastatic capacity of the tumours Gao et al. 2011. Nedd4L is upregulated by N-myc downstream-regulated gene-1 (NDRG1) in pancreatic tissue: as a result, the Ras oncogenic pathway is inhibited by NDRG1, while the SMAD4 and PTEN tumour suppressor genes are up-regulated, and this therefore alters tumour invasion and metastasis in pancreatic tumours Kovacevic et al. 2012. Clearly, decreased expression of NDRG-1 and thereby downregulation of Nedd4L increase the malignant potential of pancreatic tumours. Interestingly, patients with Sezary syndrome demonstrate significantly accentuated expression of Nedd4L (Booken et al. 2008). Downregulation of Nedd4L correlates with aggressive progression of malignant gliomas (He et al. 2012. Likewise, Wnt/beta-catenin activation leads to upregulation of Nedd4L in hepatic tissue. Altered Wnt/beta-catenin activation and thereby dis-regulated Nedd4L expression can play a role in the pathogenesis of hepatocellular carcinomas (Lee et al. 2007. Based upon the observations noted here it is clear taht Clearly, Nedd4L expression and regulation plays a key role in the pathogenesis of several tumours in addition to the gallbladder cancers. Hopefully, the coming few years will see the development of novel new agents that can alter Nedd4L expression and thereby attenuate the malignant potential of tumours.

ARID1A expression loss in gastric cancer: pathway-dependent roles with and without Epstein–Barr virus infection and microsatellite instability

The AT-rich interactive domain 1A gene (ARID1A), which encodes one of the subunits in the Switch/Sucrose Nonfermentable chromatin remodeling complex, carries mutations and is responsible for loss of protein expression in gastric carcinoma, particularly with Epstein-Barr virus (EBV) infection and a microsatellite instability-high phenotype. We used immunohistochemistry to investigate the significance of ARID1A loss in 857 gastric carcinoma cases, including 67 EBV(+) and 136 MLH1-lost gastric carcinomas (corresponding to a microsatellite instability-high phenotype). Loss of ARID1A expression was significantly more frequent in EBV(+) (23/67; 34%) and MLH1-lost (40/136; 29%) gastric carcinomas than in EBV(-)MLH1-preserved (32/657; 5%) gastric carcinomas (P < 0.01). Loss of ARID1A correlated with larger tumor size, advanced invasion depth, lymph node metastasis, and poor prognosis in EBV(-)MLH1-preserved gastric carcinoma. A correlation was found only with tumor size and diffuse-type histology in MLH1-lost gastric carcinoma, but no correlation was observed in EBV(+) gastric carcinoma. Loss of ARID1A expression in EBV(+) gastric carcinoma was highly frequent in the early stage of gastric carcinoma, although EBV infection did not cause downregulation of ARID1A: EBV-positive nasopharyngeal carcinomas (n = 8) and lymphomas (n = 15) failed to show loss of ARID1A, and EBV infection did not cause loss of ARID1A in gastric carcinoma cell lines. Taken together, loss of ARID1A may be an early change in carcinogenesis and may precede EBV infection in gastric epithelial cells, while loss of ARID1A promotes cancer progression in gastric cancer cells without EBV infection or loss of MLH1 expression. Loss of ARID1A has different and pathway-dependent roles in gastric carcinoma.

Role and clinicopathologic significance of CXC chemokine ligand 16 and chemokine (C-X-C motif) receptor 6 expression in gastric carcinomas

The chemokine ligand CXC chemokine ligand 16 and its receptor chemokine (C-X-C motif) receptor 6 are up-regulated in many types of cancer and give rise to more aggressive behavior by regulating proliferation and angiogenesis. To clarify the role and clinicopathologic significance of CXC chemokine ligand 16 and chemokine (C-X-C motif) receptor 6 expression in gastric carcinoma, their expression was examined by immunohistochemistry of tissue microarrays containing gastric carcinoma and nonneoplastic mucosa, reverse transcription-polymerase chain reaction, and Western blotting and by enzyme-linked immunosorbent assay to determine the CXC chemokine ligand 16 concentration in serum. Expression was compared with the clinicopathologic features of the carcinomas. All carcinoma and epithelial cells showed CXC chemokine ligand 16 and chemokine (C-X-C motif) receptor 6 messenger RNA expression to various degrees. Among 28 pairs of gastric carcinoma and normal tissues, there was higher CXC chemokine ligand 16 expression in carcinoma than in adjacent mucosa (P < .05), whereas the converse was true for chemokine (C-X-C motif) receptor 6 (P < .05). Nuclear CXC chemokine ligand 16 expression correlated inversely with the depth of invasion, lymphatic invasion, Union Internationale Contre le Cancer stage, and favorable prognosis. The serum CXC chemokine ligand 16 concentration was lower in male patients or patients 55 years or older than in female or younger patients, respectively (P < .05). Patients with lymphatic invasion or mixed-type carcinoma showed lower CXC chemokine ligand 16 concentrations than those with no lymphatic invasion or with diffuse-type carcinoma (P < .05). Aberrant expression of CXC chemokine ligand 16 and chemokine (C-X-C motif) receptor 6 might be involved in gastric carcinogenesis. The expression and serum concentration of CXC chemokine ligand 16 could indicate the aggressiveness and prognosis of gastric carcinomas.

P-0029 Clinicopathological Significance and Expression of KiSS-1 and MMP-9 in Gastric Carcinoma and the Precancerous Lesions

ABSTRACT Introduction To explore the relationship between KiSS-1 and MMP-9 expression in gastric carcinomas (GC); to analyze the correlation between KiSS-1 and MMP-9 expression in gastric carcinoma and relations with clinicopathological features and clinical outcomes of patients. Methods Clinical materials: 164 cases of surgically resected gastric carcinoma (GC) specimens, 164 normal gastric mucosa, 42 chronic atrophic gastritis (CAG), 93 intestinal metaplasia (IM) and 15 dysplasia (Dys) were collected from the First Affiliated Hospital of China Medical University. Immunohistochemical method was used, with mouse monoclonal antibodies against human KiSS-1 (working dilution 1:300) and MMP-9, to detect the expression of KiSS-1 and MMP-9 in normal gastric mucosa, IM, Dys and GCs. Immunohistochemical staining results assessment: Specific immunoreactivity of KISS-1 was located in the nucleus of carcinoma cells. Specific immunoreactivity of MMP-9 was located in the cytoplasm of carcinoma cells. Grading of immunostaining results: 200 cells from two selected representative fields of each sample were counted by two independent observers. The positive expression of KiSS-1 in the normal gastric mucosa as a benchmark, the expression of KiSS-1 in GCs is divided into four groups: full-negative group A, the expression of normal gastric mucosa and GC were negative, 22 cases; no changes group B, the expression of normal gastric mucosa and GC showed no significant, 59 cases; down regulation group C, the expression in GC was lower than paired normal gastric mucosa,55 cases; up regulation group D, the expression in GC was higher than paired normal gastric mucosa, 26 cases. Results The positivity rate of KiSS-1 expression was significantly lower in GCs (67.90%, 110/162) than in normal gastric (83.59%, 136/162), CAG (90.04%, 38/42) and IM (83.87%, 78/93), P 0.05). In intestinal type gastric cancer (90.48%, 38/42) the positive expression was significantly higher the diffuse-type gastric cancer (74.11%, 83/112) (P 0.05). Conclusion Decreased expression of KiSS-1 and increased expression of MMP-9 exist in GCs, and is related to certain clinicopathological parameters, suggesting they play important roles in gastric carcinogenesis. The further study is needed to explore the relevant molecular mechanism.

P-0032 Overexpression of Yes-Associated Protein 1 Contributes to the Progression and Poor Prognosis of Gastric Carcinomas

IntroductionYes-associated protein 1 (YAP1) has been shown to be a candidate oncogene and identified that it could induce the transcription of many genes. This study aimed to explore the clinicopathologic significance and correlations with carcinogenesis, metastasis and prognosis of gastric carcinoma. MethodsThe immunohistochemical method was used to detect YAP1, ki67 and c-myc expressions in gastric carcinoma and its precancerous lesions and analyze the correlations of protein expressions with clinicopathologic significance and prognosis of gastric carcinoma. ResultsThe positive rate of YAP1 expression in gastric carcinoma was significantly higher than that in normal gastric mucosa (19.2%, 32/167), chronic atrophic gastritis (25.0%, 10/40) and intestinal metaplasia (39.7%, 29/73), respectively (P<0.05). In gastric cancer with lymph node metastasis, the positive rate of YAP1 (72.8%, 115/158) was significantly higher than that in the group without lymph node metastasis (57.1%, 32/56), (P<0.05). The expression of YAP1 protein was statistically correlated with the expression of c-myc and ki67 proteins, respectively, rk=0.347; 0.204, P<0.05. Patients with YAP1 positive tumors tended to have poorer prognosis than those with negative tumors (P=0.004). Multivariate cox proportional hazards regression of 191 patients with gastric carcinoma indicated that YAP1 overexpression (P=0.043, hazard ratio [HR] 1.676), invasion depth (P=0.003 HR 1.543) and lymph node metastasis (P<0.001, HR 3.080) were high hazard factors for gastric carcinoma. ConclusionYAP1 overexpression was related to the progression and poor prognosis of gastric carcinoma and YAP1 may promote lymph node metastasis, as an adjuvant factor for predicting lymph node metastasis of gastric cancer.

Comparison of four immunohistochemical tests and FISH for measuring Her2 expression in gastric carcinomas

: Accurate testing for HER2 is essential to identify patients who are likely to benefit from trastuzumab therapy. Although comparative studies on the performance of commercially available immunohistochemistry (IHC) antibodies for HER2 have been performed in breast cancer, similar studies have not been done in gastric carcinoma (GC) thus far. : Quadruplicate tissue microarrays (TMAs) of 289 advanced GCs were immunostained with HercepTest, A0485, 4B5 and CB11, and the results were compared to those of gene amplification by fluorescence in situ hybridisation (FISH). : HER2 was amplified by FISH in 38 (13.2%) GCs. HER2 overexpression (2+ or 3+) was observed in 40 (13.8%) cases by HercepTest, 46 (15.9%) by A0485, 40 (13.8%) by 4B5 and 27 (9.3%) by CB11. The sensitivity and specificity of IHC compared to FISH was 78.9%/96% for HercepTest, 86.5%/94.4% for A0485, 76.3%/95.6% for 4B5 and 60.5%/98.4% for CB11. Focal HER2 gene amplification was more common in GCs with no (0 and 1+) or low (2+) HER2 expression. Discordant IHC results were seen in 23 cases (8.0%) with the four antibodies. All HER2 3+ cases (n = 22) by HercepTest were positive with A0485 and 4B5, while one was negative with CB11. CB11 was found to be negative in 10 HercepTest 2+ and FISH+ cases. : Focal HER2 gene amplification is more common in GCs with no or low expression of HER2. Although the specificity and positive predictive value of CB11 for FISH is highest, it lacks sufficient sensitivity to be used as a first line screening test to assess HER2 status in GCs.

Amplification of HER2 gene in gastric carcinoma detected by dual in-situ hybridization

To explore the status of HER2 gene amplification and its product HER2 protein expression in gastric carcinoma, so as to aid in patient selection for anti-HER2 targeted chemotherapy. Eighty-five cases of gastric carcinoma biopsy tissues were collected. The status of HER2 gene amplification was detected by dual in situ hybridization (dual-ISH). And HER2 protein was detected by immunohistochemistry. HER2 gene amplification was detected in 10/85 (11.8%) cases of gastric carcinoma, and no amplification was detected in 75/85 (88.2%) cases. In the 10 cases with HER2 amplification, HER2 immunoreaction scorings of 3+, 2+ and 0/1+ were present in 7, 2 and 1 cases, respectively. In the 75 cases without HER2 amplification, HER2 immunoreaction scorings of 3+, 2+ and 0/1+ were present in 0, 18 (24.0%) and 57 (76.0%) cases, respectively. Histologically, most gastric carcinoma with amplification of HER2 gene was moderately differentiated tubular adenocarcinoma. HER2 gene dual-ISH technique is a reliable and objective method for detecting HER2 gene amplification in gastric carcinoma biopsy. Clinically, only few gastric carcinomas show HER2 gene amplification and are suitable candidates for anti-HER2 targeted chemotherapy.