Prognosis Of Gastric Carcinoma Research Articles

Abstract A25: microRNAs associated with chemoresistance in gastric cancer patients tumors treated with neoadjuvant chemoterapy

Abstract Abstract: Results of randomized controlled studies conducted to verify the effectiveness of neoadjuvant chemotherapy (NC) for gastric carcinoma (GC) have suggested that this treatment is therapeutically useful for the patients instead of surgery alone. However, in some patients with apparently the same molecular and histological tumor characteristics, the objective clinical response with NC is not achieved, and this lack of response may delay curative surgery and the toxicity induced by chemotherapy may increase surgical complications. Therefore, the main challenge for improving clinical outcomes is to understand the molecular mechanisms that may play essential roles in patients' responses of GC treatments. So, predictive novel molecules identification may be crucial for correct patients' selection. Emerging evidence suggested that some microRNAs (miRNAs) can have prognostic and diagnostic value in many types of cancer. Expression levels of several miRNAs have been found to be correlated with GC prognosis and could determine the clinical response for neoadjuvant chemotherapy. Objective: Our goal was to analyze the association between tumor miRNA expression and the pathological response grade of gastric carcinoma patients treated with neoadjuvant chemotherapy. Methods: A total of 52 paraffined samples were selected from a retrospective database of A.C. Camargo Cancer Center: From these samples, 34 were biopsy tumor samples (collected before chemotherapy) of GC patients treated with NC and 18 were normal gastric tissue (controls). The chemotherapy schemes used in NC were epirubicin, cisplatin and fluoracil, with adaptations using docetaxel, xeloda and oxaliplatin. All patients treated with NC received chemotherapy prior the surgery, and subsequently they were submitted to a complete resection (R0). To determine the tumor response of patients treated of neoadjuvant chemotherapy, we analyzed representative tumor slides stained with hematoxilin and eosine, and evaluated the percentage of viable tumor cells present in the gastric resection after NC. For trial analyses we used TLDA (Taqman® Low Density Array) qRT-PCR to determine the expression of 377 miRNAs. After that, validation of differentially expressed miRNAs was done by qRT-PCR using individual assays. Results: According to the percentage of viable tumor cells seen in microscopic analysis we established a graduation from 0% to 100% of viable tumor cells, being this relationship proportional inversely to treatment response. After evaluating the percentage of viable tumor cells present in gastric resection after NC, we categorized the samples in quartiles. After statistical analysis, the samples with a 100% of viable tumor cells after neoadjuvant treatment, showed us nine downregulated miRNAs. We performed qRT-PCR using individual assays, and confirmed downregulated expression of 3 miRNAs in biopsy tumor samples of patients treated with NC with 100% of viable tumor cells in gastric resection tumor. Conclusion: We found proteomic and expression profiles reports about the relationship of these 3 downregulated miRNAs with some genomic alterations involved in gastric cancer pathways and with some mechanisms of drugs resistance. These miRNA signature may be useful as potential biomarkers to predict response of gastric cancer patients to NC. Citation Format: Michelle Maccarini Barcelos-Baldoni, Claudia Malheiros Coutinho-Camillo, Renato David Puga, Maria Dirlei Ferreira-Begnami. microRNAs associated with chemoresistance in gastric cancer patients tumors treated with neoadjuvant chemoterapy. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A25.

Loss of large tumor suppressor 1 promotes growth and metastasis of gastric cancer cells through upregulation of the YAP signaling.

Accumulating evidence shows that large tumor suppressor 1 (LATS1) as a novel resident governor of cellular homeostasis is implicated in multiple tumorigenic properties including cell growth, apoptosis and metastasis. However, the contribution of LATS1 to gastric carcinoma (GC) remains unclear. The correlation of LATS1 expression with clinicopathologic characteristics, GC prognosis and recurrence was analyzed by immunohistochemistry, Univariate and Kaplan-Meier analysis. Functional experiments were performed to investigate biological behaviors of GC cells and underlying molecular mechanisms. Tumor growth and metastasis was assessed in vivo using orthotopic implantation GC models in severe combined immune deficiency (SCID) mice. Consequently, decreased LATS1 expression was significantly associated with the lymph node metastasis, poor prognosis and recurrence. Ectopic expression of LATS1 decreased GC cell proliferation and invasion in vitro and inhibited tumor growth and liver metastasis in vivo, but depletion of LATS1 expression restored the invasive phenotype. Further observation indicated that YAP pathway was required for LATS1-induced inhibition of cell growth and invasion, and LATS1 restrained nuclear transfer of YAP, downregulated YAP, PCNA, CTGF, MMP-2, MMP-9, Bcl-2 and CyclinD1 expression and upregulated p-YAP and Bax expression. Our findings suggest that LATS1 is a potential candidate tumor suppressor and inhibits the growth and metastasis of GC cells via downregulation of the YAP signaling.

Survival and prognosticators of gastric cancer patients with only positive peritoneal lavage cytology.

16 Background: Treatment strategies for only positive peritoneal lavage cytology findings have not yet been established. The objective of this retrospective study was to clarify the survival and prognosticators in these patients. Methods: Overall survival (OS) rates were examined in 39 patients with gastric cancer who underwent a curative resection and had positive peritoneal cytology in the absence of overt peritoneal metastases between January 2000 and June 2015. Univariate and multivariate analyses were performed to identify risk factors using a Cox proportional hazards model. Results: A total of 39 patients were evaluated. The median overall survival was significantly longer in the 34 patients who received chemotherapy after surgery than that in the 5 who did not (19.1 vs 5.9 months, p < 0.01). Among the patients who received chemotherapy after surgery, univariate and multivariate analyses showed that pN3b was an independent significant prognosticator (hazard ratio of 4.169 with 95% CI: 1.108-15.684, p = 0.035). The median OS was 15.8 months when the patients diagnosed with N3b was 33.1 months when the patients diagnosed with N3a or lower. Conclusions: The prognosis of gastric carcinoma with positive peritoneal lavage cytology without peritoneal metastasis is still poor and need more aggressive treatment. The lymph node metastasis was a significant prognosticator in these patients.

Expression and clinical implication of S100A12 in gastric carcinoma.

S100 protein family has been implicated in multiple stages of tumorigenesis and progression in which S100A12 is one of the subtypes. However, the role of S100A12 in gastric carcinoma (GC) has not been elucidated yet. This study was aimed to investigate the expression of S100A12 in GC tissues and evaluate the clinical significance of S100A12 in GC patients. S100A12 protein was detected in 207 GC and 52 paired non-cancerous mucosal tissues by immunohistochemistry, while messenger RNA (mRNA) was investigated by Oncomine database analysis. Moreover, survival analysis was performed and the correlation between S100A12 and ubiquitin-specific protease 10 (USP10) and p53 was determined. As for tumor cells, the expression of S100A12 protein and mRNA in GC was proved to be lower than that in non-cancerous mucosa tissues (p < 0.05). Clinicopathological analysis showed that S100A12 protein was negatively associated with tumor size (p = 0.004), depth of invasion (p = 0.022), tumor node metastasis (TNM) stage (p = 0.018), Lauren classification (p < 0.000), and cell differentiation (p < 0.000). In contrast, a positive correlation was found between S100A12 and USP10 protein (p < 0.000). However, no relationship was detected between S100A12 and p53. Moreover, the survival analysis indicated that S100A12 protein was a favorable factor of prognosis of GC (p < 0.05). Although the expression of S100A12 in the stromal cells was detected higher than that in the tumor cells, no relationship between S100A12 protein in stromal cells and the clinicopathological features described above was found (p > 0.05). Our findings suggested that low expression of S100A12 might be served as a new marker in the tumorigenesis and progression of GC.

Clinicopathologic Significance and Prognostic Value of B7 Homolog 1 in Gastric Cancer: A Systematic Review and Meta-Analysis.

Immunologic checkpoint marker B7 homolog 1 (B7-H1) plays a fundamental role in the initiation and progression of gastric cancer (GC); however, the clinicopathologic significance and prognostic value of B7-H1 in GC remains controversial. In this study, we aimed to assess their relationship through a meta-analysis.Medline/PubMed, EMBASE, the Cochrane Library databases, and Grey literature were searched up to August 10, 2015, for eligible studies of the association between B7-H1 expression and overall survival in GC. The hazard ratio and its 95% confidence interval (CI) were calculated from the included studies. Moreover, the odds ratio (OR) was also extracted to evaluate the association between the clinicopathologic parameters of participants and B7-H1 expression.Five studies involving 481 patients were included in the meta-analysis. The pooled results showed that positive B7-H1 expression was a negative predictor for overall survival with hazard ratio of 1.74 (95% CI: 1.40–2.17; Pheterogeneity = 0.146) in GC. Additionally, increased B7-H1 was found to be significantly associated with positive lymph node metastasis (OR = 2.61, 95% CI: 1.78–3.84; Pheterogeneity = 0.004) and poorer tumor stage (OR = 2.28, 95% CI: 1.39–3.74; Pheterogeneity = 0.006); however, higher B7-H1 expression was not significantly correlated with poorer tumor differentiation (OR = 1.29, 95% CI: 0.90–1.86; Pheterogeneity = 0.013) and bigger tumor size (OR = 1.18, 95% CI: 0.81–1.73; Pheterogeneity = 0.104).The meta-analysis suggested that B7-H1 could act as a significant biomarker in the poor prognosis of gastric carcinoma.

Overexpression of 3-phosphoinositide-dependent protein kinase-1 is associated with prognosis of gastric carcinoma.

This study investigated the correlation between the expression of 3-phosphoinositide-dependent protein kinase-1 (PDK1) and the prognosis of gastric carcinoma patients. A total of 156 paired tumor and matched normal samples were collected from patients of gastric carcinoma who underwent surgical resection. The expression of PDK1 was analyzed by real-time quantitative PCR and immunohistochemistry method. Potential correlation between PDK1 protein expression and the clinicopathological characteristics was determined by chi-square test and Spearman correlation analysis. The influence of PDK1 expression on 5-year survival rate and survival length was determined by Kaplan-Meier analysis. The expression of PDK1 mRNA and protein were significantly higher in tumor samples comparing to those in adjacent normal samples (paired t test, P = 0.007). Immunohistochemical staining results indicated that PDK1 protein level was positively correlated with infiltration (P = 0.006). However, no associations with age, sex, clinical stage, lymph node metastasis, and distant metastasis were observed (P > 0.05). The 5-year survival rate was 20.1 and 63.4% of the patients with high and low expression level of PDK1, respectively (P < 0.05). The median survival length was 32.5months (95% CI 22.8-37.6) for patients with high level of PDK1 and 63.1months (95% CI 52.3-64.7) for patients with low level of PDK1 (×2 = 20.153, P < 0.05). Kaplan-Meier survival curves demonstrated that elevated expression of PDK1 was an independent negative prognostic factor of gastric carcinoma (P<0.05). Our study indicated that PDK1 might serve as a candidate pro-oncogene and a potential prognostic biomarker for gastric carcinoma.

Abstract 661: Increasing sensitivity of SAIT301, a specific monoclonal antibody of c-Met, with paclitaxel combination in c-Met positive gastric cancer

Abstract The c-Met is frequently overexpressed and related to a worse prognosis in gastric carcinoma (GC). This study aimed to determine a c-Met targeting monoclonal antibody (SAIT301) with effects on the proliferation and to increase efficacy of SAIT301 administered in combination with paclitaxel in gastric cancer cell lines. Anticancer effect of SAIT301 was assessed using CCK-8 assay in 52 GC cell lines. c-Met status was identified using RTK array and qPCR. Cell cycle distribution was determined with flow cytometry. Expression levels of c-Met and cleaved PARP, apoptosis induction marker, were determined by western blot analysis. Combination index (CI) evaluated by CalcuSyn software. We screened 52 cell lines for growth inhibition by SAIT301.Among 11 c-Met positive GC cells, 5 cell lines were sensitive to SAIT301 (5/11, 45%) with 40∼60% inhibition rate at 5 μg/ml.SAIT301 sensitivity of 5 cell lines has a tendency of correlation between MET amplification, c-Met/p-Met co-expression, low Cbl level or exon14 deletion of MET. Next, we performed combination treatment with SAIT301 and paclitaxel in 5 cell lines. The results exhibited increasing anti-proliferative effects with synergism. In cell cycle analysis, SAIT301 increased the percentage of cells in the G1 phase, while paclitaxel increased the G2/M phase(3-19%). Combination of SAIT301 and paclitaxel significantly increased in sub G1(2-17%) and G2/M arrest(4-19%). Western blot analysis showed paclitaxel induced c-Met expression. In addition, SAIT301 and paclitaxel combination down-regulated c-Met expression and enhanced PARP cleavage more than monotherapy. Our results indicate that the SAIT301 combined with paclitaxel therapy had synergistic effects in the treatment of c-Met positive gastric cancer. Citation Format: Sun Kyoung Kang, Jeong Min Kim, Won Suk Lee, Woo Sun Kwon, Tae Soo Kim, Seon-hui Shim, Kyung-Ah Kim, Ho-Yeong Lim, Hyun Cheol Chung, Sun Young Rha. Increasing sensitivity of SAIT301, a specific monoclonal antibody of c-Met, with paclitaxel combination in c-Met positive gastric cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 661. doi:10.1158/1538-7445.AM2015-661

Clinical Significance of NOTCH1 and NOTCH2 Expression in Gastric Carcinomas: An Immunohistochemical Study

NOTCH signaling can exert oncogenic or tumor suppressive functions and can contribute to chemotherapy resistance in cancer. In this study, we aimed to clarify the clinicopathological significance and the prognostic and predictive value of NOTCH1 and NOTCH2 expression in gastric cancer (GC). NOTCH1 and NOTCH2 expression was determined immunohistochemically in 142 primarily resected GCs using tissue microarrays and in 84 pretherapeutic biopsies from patients treated by neoadjuvant chemotherapy. The results were correlated with survival, response to therapy, and clinico-pathological features. Primarily resected patients with NOTCH1-negative tumors demonstrated worse survival. High NOTCH1 expression was associated with early-stage tumors and with significantly increased survival in this subgroup. Higher NOTCH2 expression was associated with early-stage and intestinal-type tumors and with better survival in the subgroup of intestinal-type tumors. In pretherapeutic biopsies, higher NOTCH1 and NOTCH2 expression was more frequent in non-responding patients, but these differences were statistically not significant. Our findings suggested that, in particular, NOTCH1 expression indicated good prognosis in GC. The close relationship of high NOTCH1 and NOTCH2 expression with early tumor stages may indicate a tumor-suppressive role of NOTCH signaling in GC. The role of NOTCH1 and NOTCH2 in neoadjuvantly treated GC is limited.

Lysosomal-associated protein transmembrane 4 Beta-35 overexpression is a novel independent prognostic marker for gastric carcinoma.

ObjectiveThe purpose of this work was to analyze the relationships between the expression status of Lysosomal-associated protein transmembrane-4 beta 35 (LAPTM4B-35) in cancerous tissues and clinicopathological characteristics and prognosis of the patients with gastric carcinoma (GC).MethodsThe GC samples from 157 patients in a discovery cohort and 148 patients in a testing cohort with follow-up data were used to validate the feasibility of expression of LAPTM4B-35 protein in predicting GC prognosis. Immunohistochemical staining was used to determine the expression of LAPTM4B-35 protein in precancerous gastric lesions and gastric carcinomas. The correlation between the expression of LAPTM4B-35 and clinicopathologic characteristics of patients with gastric carcinoma was analyzed using chi-square test. Univariate and multivariate analyses were performed to determine the association between LAPTM4B-35 expression and prognosis.ResultsLAPTM4B-35 expression was increased steadily in sequential stages of precancerous gastric lesions. Positive LAPTM4B-35 expression was more frequently detected in patients with distant metastasis (P = 0.023) and III+IV TNM stages (P = 0.042) in the discovery cohort. Kaplan-Meier survival curves and univariate analysis showed that expression of LAPTM4B-35 had a significant impact on overall survival of patients with gastric carcinoma in discovery cohort (P<0.001) and testing cohort (P = 0.001). LAPTM4B-35 expression was an independent prognostic indicator for the overall survival of patients with gastric carcinoma in both cohorts.ConclusionsThe present research demonstrated that LAPTM4B-35 over-expression was an independent factor in gastric carcinoma prognosis. LAPTM4B gene may be a useful target of interventions slowing the progression of precancerous gastric lesions and a new therapy method to improve the prognosis of gastric carcinoma.

Expression of erythropoietin producing human hepatocellular receptor A2 and CD133 in gastric carcinoma and their correlation with development of gastric cancer

Objective To analyze the expression of erythropoietin producing human hepatocellular receptor A2(EphA2)and CD133 in gastric carcinoma and their relationship with clinicopathological features and the prognosis of gastric carcinoma. Methods Envision immunohistochemical method was used to assess the expression of EphA2 and CD133 in 82 cases of human gastric carcinoma tissues and non-cancerous adjacent gastric tissues. Results The expression rate of EphA2 in gastric carcinoma tissues was higher than that in non-cancerous adjacent gastric tissues(86.59% vs.20.73%,P< 0.01). The expression rate of CD133 in gastric carcinoma tissues was higher than that in non-cancerous adjacent gastric tissues(67.07% vs.10.98%,P< 0.01).The expression of Eph A2 was related to TNM stage and lymph node metastasis of gastric carcinoma(P< 0.05). There was a close correlation between the expression of CD133 and histological grade, TNM stage and lymph node metastasis(P<0.05). Conclusion The overexpression of EphA2 and CD133 may play certain roles in the pathogenesis of gastric carcinoma. Key words: Gastric carcinoma; Eerythropoietin producing human hepatocellular receptor A2; CD133; Immunohistochemical method

Usefulness of the Log Odds of Positive Lymph Nodes to Predict and Discriminate Prognosis in Gastric Carcinomas

BackgroundThe lymph node ratio (LNR) and log odds of positive lymph nodes (LODDS) have been proposed to minimize the stage migration phenomenon. The value of the LODDS and LNR staging systems to predict and discriminate prognosis was assessed and compared to the International Union Against Cancer (UICC) TNM classification (pN). MethodsThree hundred and twenty-six patients with gastric carcinoma were retrospectively studied. Disease-specific survival rates were calculated for every pN, LNR, and LODDS category. ResultsFour LNR categories (0, 1–25, 26–75, and >76 %) and four LODDS categories (−5 to −3, > −3 to −1, > −1 to 3, and >3 to 5) were established. In the multivariate analysis, only the stage pT3-4 versus pT1-2 (HR 1.88, 95 % CI 1.11–3.20, p = 0.02) and LODDS as continuous variable (HR 1.40, 95 % CI 1.21–1.61, p < 0.001) remained as independent prognostic factors. In patients with <16 lymph nodes retrieved, only the LODDS system could discriminate different disease-specific survival curves for every category. LODDS categories were able to discriminate subgroups with different prognoses in pN stages and LNR categories. ConclusionsThe LODDS staging system was superior to the pN classification and LNR system to discriminate risk prognosis especially in patients with an insufficient number of retrieved lymph nodes.

Expression levels of matrix metalloproteinase-9 in human gastric carcinoma.

The present report investigated the correlation between the expression levels of matrix metalloproteinase (MMP)-9 in gastric carcinoma patients and the clinicopathological characteristics. Forty-five samples of gastric carcinoma and distal gastric mucosa tissue, and 10 samples of healthy gastric mucosa tissue were analyzed using semi-quantitative polymerase chain reaction, as well as immunohistochemical and hematoxylin and eosin staining. MMP-9 protein levels in serum samples from the same patients were quantified by enzyme-linked immunosorbent assay. The present report identified that MMP-9 expression was markedly higher in the gastric carcinoma tissue (86.67%) than in the adjacent healthy tissue (10.00%). A positive association was identified between the level of MMP-9 protein expression and the depth of cancer invasion (P<0.05). Furthermore, the preoperative serum levels of the MMP-9 protein in the gastric carcinoma tissue were correlated with the tumor-node-metastasis stage and occurrence of lymph node metastasis (P<0.01). Data from the present report indicates that MMP-9 may be key in gastric carcinoma malignancy, and implies that MMP-9 may serve as a novel biomarker in the diagnosis and prognosis of gastric carcinoma.

SMYD3 overexpression was a risk factor in the biological behavior and prognosis of gastric carcinoma.

SET and MYND domain-containing protein 3 (SMYD3), a histone methyltransferase, plays a key function in the progression of human cancer. However, the role of SMYD3 in gastric carcinoma carcinogenesis has yet to be elucidated. This study aimed to determine the relationships of SMYD3 expression with clinicopathological characteristics and prognosis in gastric carcinoma. The expression of SMYD3 was detected by real-time quantitative reverse transcription PCR and Western blot in gastric carcinoma (GC) cell lines, normal gastric mucosa cell line, GC tissues, and adjacent non-tumor tissues. SMYD3 expression in tissue sections of 180 gastric carcinoma samples were evaluated using immunohistochemistry. The staining results were compared with clinicopathological characteristics and to the outcome of patients. The expression levels of SMYD3 messenger RNA (mRNA) and protein in GC tissues were both higher than those in adjacent non-tumor tissues (p < 0.05). SMYD3 mRNA and protein expression levels were higher in GC cell lines MKN28, SGC7901, and MGC803 than normal gastric mucosa cell line GES-1. SMYD3 expression in gastric carcinoma was significantly correlated with primary tumor size (p < 0.001), lymph node metastasis (p < 0.001), and TNM stage (p = 0.011). Degree of differentiation [hazard ratio (HR) = 5.113; p = 0.006], serosal invasion (HR = 2.074; p = 0.024), lymph node metastasis (HR = 1.354; p < 0.001), and SMYD3 expression (HR = 0.564; p = 0.004) were identified as the independent factors of the overall survival (OS) in all enrolled GC patients. For patients with positive lymph node metastasis, degree of differentiation (HR = 5.974; p = 0.015), lymph node metastasis (HR = 1.257; p < 0.001), and SMYD3 expression (HR = 0.529; p = 0.004) were the independent prognostic factors of the OS. SMYD3 performed an important function in the aggressiveness of gastric carcinoma and may act as a promising target for prognostic prediction.

High expression of astrocyte elevated gene-1 is associated with clinical staging, metastasis, and unfavorable prognosis in gastric carcinoma.

More and more evidence has demonstrated that astrocyte elevated gene-1 (AEG-1) is tightly associated with progression, metastasis, and unfavorable prognosis in many malignancies. However, the potential biological role of AEG-1 in gastric carcinoma (GC) has not been thoroughly delineated. In the current study, we found that AEG-1 mRNA and protein levels in GC tissues were significantly higher than those in normal gastric mucosa (P < 0.05). Simultaneously, statistical analysis displayed a significant correlation of high AEG-1 mRNA and protein expressions with differentiation status, TNM staging, invasive depth, and lymph node metastasis (P < 0.05). Most importantly, expressions of AEG-1 mRNA and protein in high clinical staging and metastatic GC tissues were dramatically higher than those in low clinical staging and non-metastatic GC tissues (P < 0.05). Stepwise investigation confirmed that the survival time of the patients with high AEG-1 level was shorter than those with low AEG-1 level or negative AEG-1 staining. Taken altogether, our data presented herein suggest that AEG-1 may be a novel predictor for metastasis and prognosis of the patients with GC.

Prognostic significance of expression of CD133 and Ki-67 in gastric cancer.

CD133 is one of the most important stem cell markers in solid cancers and Ki-67 is a marker that reflects cell proliferation. The relationships between the expression of CD133 and Ki-67 and prognosis in gastric carcinoma are unknown and need exploring. We examined 50 gastric cancer patients retrospectively in the Radiation Oncology Department of the Faculty of Medicine, Gazi University. CD133 and Ki-67 expression was examined using immunohistochemical staining. The survival rate in patients with CD133 positive expression was significantly worse than that in the patients with negative expression (p=0.04). Expression of CD133 had a positive correlation with that of Ki-67 (r=0.350; p=0.014). Multivariate analysis revealed that the expression of CD133 was an independent prognostic factor in gastric cancer (p=0.02). Conclusion, expression of CD133 may be a useful prognostic marker in gastric cancer.

WWP1 as a potential tumor oncogene regulates PTEN-Akt signaling pathway in human gastric carcinoma.

Whelming evidence has demonstrated that WW domain containing E3 ubiquitin protein ligase 1 (WWP1) participates in a wide variety of biological processes and is tightly related to the initiation and progression of many tumors. Currently, although mounting evidence supports a role of WWP1 in tumor promotion and tumorigenesis, the potential roles of WWP1 and its biological functions in gastric carcinoma are not fully understood. Here, we found that WWP1 messenger RNA (mRNA) and protein were highly expressed in gastric carcinoma tissues and cells. High WWP1 mRNA and protein levels were tightly related to differentiation status, TNM stage, invasive depth, lymph node metastasis, and poor prognosis in gastric carcinoma. Furthermore, WWP1 siRNA significantly decreased WWP1 protein level in MKN-45 and AGS cells; meanwhile, WWP1 depletion markedly inhibited tumor proliferation in vitro and in vivo, arrested cell cycle at G0/G1 phase, and induced cell apoptosis in MKN-45 and AGS cells. Most notably, WWP1 downregulation both inactivated PTEN-Akt signaling pathway in MKN-45 and AGS cells. Taken altogether, our findings suggest that WWP1 acts as an oncogenic factor and should be considered as a novel interfering molecular target for gastric carcinoma.

Prognosis significance of HER2 status and TACC1 expression in patients with gastric carcinoma.

HER2 amplification and/or expression occurs in gastric carcinoma (GC), but the role of HER2 in the prognosis of GC remains unclear. The dysregulation of transforming acidic coiled coil 1 (TACC1), a downstream gene of HER2, is thought to be involved in the development of GC. The aim of this study was to investigate the role and relationship of HER2 and TACC1 in GC. The expression of HER2 and TACC1 was analyzed using immunohistochemistry on 129 primary resected GC patients, and HER2 amplification was additionally determined by FISH. The data on clinicopathological features and relevant prognostic factors in these patients were analyzed. The expression (3+, 2+ and 1+) and the amplification of HER2 was observed in 57 cases (44.2 %) and 25 cases (19.4 %), respectively, and the correlation between HER2 expression and amplification was strong (p < 0.001). According to the FDA criteria, 24 cases (18.6 %) would have been considered as HER2 positive. A total 62 (48.1 %) GC tissues showed positive cytoplasmic staining of TACC1. There was a significant and positive association between TACC1 and HER2. HER2 positive was significantly associated with TNM stage (p = 0.019), and TACC1 expression was significantly associated with lymph node metastasis (p = 0.004) and TNM stage (p = 0.004). TNM stage, TACC1 expression and co-positive of both HER2 and TACC1 were independent prognostic factors. TACC1 expression is an independent prognostic indicator of GC. The correlation between TACC1 expression and HER2-positive status indicated a possible synergistic regulation of the two molecules and co-positive of both HER2 and TACC1 maybe a more valuable prognostic marker.

Matrix metalloproteinase-7 mRNA and protein expression in gastric carcinoma: a meta-analysis.

Messenger RNA (mRNA) acts as template for protein synthesis. The matrix metalloproteinase-7 (MMP-7) protein and its mRNA expression have been suggested to be involved in the development of various diseases and cancers. We aimed to study associations between the MMP-7 protein and mRNA expression in gastric carcinoma (GC) patients. We searched in the Science Citation Index, the Cochrane Library, PubMed, Embase, CINAHL, Current Contents Index, and several Chinese databases. Studies were pooled and odds ratios and their corresponding 95 % confidence intervals were calculated. Subgroup analyses and publication bias detection were also conducted. Statistical analysis was performed via Version 12.0 STATA software. An updated meta-analysis based on 16 independent cohort studies was performed to investigate this association. The study suggests that significant differences in MMP-7 protein levels were observed in tumor-node-metastasis (TNM) I-II vs. III-IV (odds radio (OR) =3.19, 95 % confidence interval (95%CI) =1.59 ∼ 6.41, P=0.001), in T1-2 vs. T3-4 invasive grade (OR=1.82, 95%CI=1.07 ∼ 3.12, P=0.028), and in distant metastasis-positive vs. metastasis-negative samples (OR=3.14, 95%CI=1.05 ∼ 9.35, P=0.040). Increased MMP-7 mRNA levels were found to be significantly correlated with invasive grade (T3-4 vs. T1-2: OR=5.61, 95%CI=2.64 ∼ 11.95, P<0.001) and in the lymph node (LN) metastasis (positive vs. negative: OR=7.08, 95%CI=4.20 ∼ 11.93, P<0.001) group. Country subgroup analysis yielded significantly different estimates in the protein expression of MMP-7 of all experimental groups. MMP-7 mRNA levels were increased in LN metastasis-positive GC in contrast to metastasis-negative in China and Korea (all P<0.05); this was not shown in Japan (P>0.05). Higher protein and mRNA levels of MMP-7 were statistically associated with aggressive LN metastasis, advanced TNM stage, and invasion in GC patients; MMP-7 can thus potentially serve as a useful biomarker in determining GC progression and prognosis.

Clinicopathological and prognostic significance of p53, Ki-67, and Bcl-2 expression in Tunisian gastric adenocarcinomas

Gastric carcinoma (GC) is a highly aggressive malignancy with poor prognosis. It is widely accepted that malignancy results from abnormal cell growth due to dysregulation of the balance between cell proliferation and apoptosis. Our study aimed to investigate the clinicopathological and prognostic significance of p53, Ki-67, and Bcl-2 in Tunisian GC patients by immunohistochemistry. It was observed that the older patients showed p53 overexpression compared with the younger patients (p<0.05). There was higher p53 expression in the intestinal-type compared with the diffuse-type (p<0.05), and in well/moderate differentiated than in poor differentiated tumors. The expression of Ki-67 was positively associated with tumor size and venous invasion (p<0.05). Bcl2 expression occurred in male patients and correlated with depth of invasion (p=0.02). A Kaplan–Meier analysis indicated an inverse correlation between p53 and Ki-67 expression and the overall survival. Multivariate analysis revealed that the tumor site, Ki-67 and p53 expression were independent prognostic factors for gastric carcinomas (p<0.05). Finally, combined expression of p53, Ki-67 and Bcl-2 showed that the group of patients with tumors p53+/Ki-67+/Bcl2− had aggressive behavior and poor prognosis (p log rank=0.000). In summary, our data indicated that the expression of p53, Ki-67, and Bcl-2 may provide useful information for identifying patients with aggressive behavior and poor prognosis of GC.

Promoter methylation of Raf kinase inhibitory protein: A significant prognostic indicator for patients with gastric adenocarcinoma.

DNA methylation has an important role in the development of carcinomas. As a metastasis suppressor gene, Raf kinase inhibitory protein (RKIP) suppresses tumor cell invasion and metastasis. In the present study, the associations between RKIP protein expression and promoter methylation with clinicopathological parameters, prognosis and survival rates in gastric adenocarcinoma were investigated. RKIP protein expression and promoter methylation were measured in 135 cases of surgically resected gastric adenocarcinoma specimens and corresponding normal tissues using immunohistochemistry and methylation-specific polymerase chain reaction, respectively. Kaplan-Meier analyses were performed to analyze the patient survival rate. Prognostic factors were determined using multivariate Cox analysis. RKIP promoter methylation was detected in 48.9% of gastric carcinoma tissues and 5.17% of adjacent tissues (P<0.05). RKIP protein expression was detected in 43.0% of gastric carcinoma tissues and 91.1% of adjacent tissues (P<0.05). The protein expression levels and promoter methylation of RKIP were shown to correlate with pathological staging, Union for International Cancer Control-stage, tumor differentiation and lymph node metastasis (P<0.05). In addition, the protein expression of RKIP in gastric carcinomas was demonstrated to be associated with promoter methylation of RKIP. Survival analysis of gastric carcinoma patients revealed that promoter methylation in RKIP-positive tumors correlated with a significantly shorter survival time when compared with RKIP-negative tumors (P=0.0002, using the log-rank test). Using multivariate Cox analysis, promoter methylation of RKIP was shown to be an independent prognostic factor (P=0.033). These results indicated that abnormal promoter methylation of RKIP may be one cause of downregulated RKIP expression. Downregulation of RKIP expression was shown to correlate with the incidence and development of gastric carcinomas. Thus, abnormal promoter methylation of RKIP may be a valuable biomarker for estimating gastric carcinoma prognosis.