Ma G.,Nanjing Medical University |
Liu H.,Nanjing Medical University |
Hua Q.,Nanjing Medical University |
Wang M.,Nanjing Medical University |
And 9 more authors.
Molecular Cancer | Year: 2017
Background: Inactivation of tumor suppressor genes by promoter hypermethylation plays a key role in the tumorgenesis. It is necessary to uncover the detailed pattern of whole genome-wide abnormal DNA methylation during the development of gastric cancer (GC). Method: We performed a genome-wide methylation detection using 12 paired of GC tissues and their corresponding normal tissues. Methylation-specific PCR (MSP) and bisulphite sequencing (BSP) were used to measure methylation status of specific CpG site. Based on the bioinformatic analysis, the cell phenotypes and mouse model experiments were constructed to detect effect of the target gene. Using the Kaplan-Meier survival curve, the clinical value of KCNMA1 was assessed in GC patients. Results: The CpG site cg24113782 located at the promoter of KCNMA1 showed the most significant difference, contributing to the commonly silenced KCNMA1in gastric cancer cells and primary GC tissues. The promoter methylation of KCNMA1 was detected in 68.7% (77/112) of tumor tissues, compared with 16.2% (18/112) of normal tissues (P < 0.001). The survival curve indicated that KCNMA1 hypermethylation was significantly associated with the shortened survival in GC patients (P = 0.036). KCNMA1 significantly inhibited biological malignant behavior of gastric cancer cell by inducing cell apoptosis in vitro, and suppressed xenograft tumor growth in subcutaneous mouse models (both P < 0.001). Furthermore, the anti-tumor effect of KCNMA1was mediated through suppressing the expression of PTK2. Conclusion:KCNMA1 is a critical tumor suppressor in gastric carcinogenesis and its hypermethylation is an independent prognostic factor in patients with gastric cancer. © 2017 The Author(s).
Wang S.,Nanjing Medical University |
Tian Y.,Nanjing Medical University |
Wu D.,Nanjing Medical University |
Zhu H.,Nanjing Medical University |
And 6 more authors.
Mutagenesis | Year: 2012
Gastric cancer is the second leading cause of cancer-related death worldwide with a low 5-year survival (S5y) after initial diagnosis. Although aberrant Wnt/β-catenin (CTNNB1) signaling has been observed in multiple human cancers, there is no information on the role of CTNNB1 polymorphisms in gastric cancer risk and S5y. We performed a genetic association study to analyse the correlation between the five tagged SNPs (tSNPs) (rs4135385, rs1798808, rs1880481, rs11564465 and rs2293303) of CTNNB1 and gastric cancer risk and survival. A total of 944 patients with complete follow-up information and 848 cancer-free controls were enrolled in this study. The rs1880481 polymorphism was correlated with decreased risk of gastric cancer [AC/AA vs. CC: adjusted odds ratio (OR) = 0.76, 95% confidence interval (CI) = 0.63-0.91], whereas the three other SNPs showed opposite effect (AG/AA vs. GG: adjusted OR = 1.31, 95% CI = 1.08-1.57 for rs4135385; GG vs. AA/AG: 2.09, 1.02-4.28 for rs11564475; TT vs. CC/CT: 4.87, 2.72-8.71 for rs2293303). We further investigated if these tSNPs were related to the S5y of gastric cancer, and the results displayed that only the SNP rs4135385 AG/AA genotypes were significantly associated with a favorable gastric cancer survival compared with the GG genotype [adjusted hazard ratio (HR) = 0.80, 95% CI = 0.66-0.97], and the association was more prominent among patients with non-cardia gastric cancer (NCGC) than those with cardia gastric cancer (CGC) (Log-rank P = 0.007 for NCGC and 0.417 for CGC). Our results indicated that the genetic variants of CTNNB1 could be used as predictors of gastric cancer susceptibility and prognosis. © The Author 2012. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved.
Chen L.-J.,Suzhou University |
Sun J.,Suzhou University |
Wu H.-Y.,Suzhou University |
Zhou S.-M.,Yixing Tumor Hospital |
And 5 more authors.
Cancer Immunology, Immunotherapy | Year: 2011
A retrospective cohort study including 112 patients suffering from esophageal squamous cell carcinoma (ESCC) was performed to investigate the expression of B7-H4 in ESCC and determine its association with patient's clinicopathological parameters and survival. Expression levels of B7-H4 on tumor cells and densities of tumor infiltrating lymphocytes (TILs) in the surgical specimens of ESCC tissues were characterized using immunohistochemical assays. Uni- and multivariate analyses were performed to evaluate the prognostic value of B7-H4 expression levels and densities of TILs in tumor sections. Positive B7-H4 immunostaining was observed in 107 of 112 (95.5%) of ESCC tissue sections. We further divided all patients into two major subgroups, a lower B7-H4 expression group with 46 patients and a higher B7-H4 expression group with 66 patients. We found that expression levels of B7-H4 on tumor cells were significantly correlated with patient's gender (P = 0.0288), distant metastasis (P = 0.0500), and TNM stage (P = 0.0258). Moreover, tumor cell B7-H4 expression was inversely correlated with densities of CD3+ T cells in tumor nest (P = 0.0424) and CD8+ T cells in tumor stroma (P = 0.0229). The overall survival rate of the patients with higher B7-H4 expression was significantly worse than that of the patients with lower B7-H4 expression (P = 0.0105, Hazard Ratio: 1.854, 95%CI:1.152-2.902). Markers of cell-mediated immune responses such as CD3, CD8, and T-bet were associated with better patient survival. The present study demonstrated that B7-H4 expression in human ESCC is associated with cancer progression, reduced tumor immunosurveillance and worse patient outcomes. B7-H4 can serve as a novel prognostic predictor for human ESCC and a potential target for the immune therapy against this malignancy. © 2011 Springer-Verlag.
Wang D.,Yixing Tumor Hospital |
Qin Q.,Nanjing Medical University |
Jiang Q.-J.,Yixing Tumor Hospital |
Wang D.-F.,Yixing Tumor Hospital
Journal of X-Ray Science and Technology | Year: 2016
Radiation therapy is a typical treatment for esophageal squamous cell carcinoma (ESCC), especially middle and upper segment esophagus, and inoperable patients. However, how to promote radiation sensitivity in radio-resistant cancer cells is a conundrum. Here, our study investigated the radiosensitizing effect of bortezomib, a specific and reversible dipeptide boronic acid analog, in ESCC cells. Human esophageal squamous carcinoma cell lines Eca109 and TE-13 were exposed to hypoxia and/or ionizing radiation (IR) with or without treatment of bortezomib. Cell proliferation assay was performed with CCK8. Cell apoptosis and cell cycle assay were performed with flow cytometry. The radiosensitization effect of was assessed by clonogenic survival and progression of tumor xenograft. The expression of HIF-1α, VEGF, and apoptosis proteins was evaluated by Western blot. Radiation-induced DNA double strand break and homologous recombination repair were assessed by immunofluorescence. Our results show that bortezomib efficiently radiosensitizes ESCC cells by decreasing the expression of HIF- 1α and VEGF, inducing apoptosis by activating caspase, and delaying DNA damage repair after radiation. © 2016 -IOS Press and the authors. All rights reserved.
Wang S.,Nanjing Medical University |
Tao G.,Nanjing Medical University |
Wu D.,Nanjing Medical University |
Zhu H.,Core Laboratory of Nantong Cancer Hospital |
And 7 more authors.
Molecular Carcinogenesis | Year: 2013
Genetic variations in miRNAs have been demonstrated to be capable of altering miRNA expression, consequently affecting many cancer-related biological processes. The MIR196A2 rs11614913 (T>C) polymorphism has been reported to be associated with various cancers development and progression. In our study, we aim to explore whether this polymorphism is relevant to the genetic susceptibility and prognosis of gastric cancer in a Chinese population. We analyzed the correlations of rs11614913 polymorphism with gastric cancer susceptibility in test and validation sets. The test set comprised 749 cases and 900 controls, while the validation set enrolled 940 cases and 1046 controls. Moreover, we evaluated the association between the polymorphism and gastric cancer prognosis in the validation set with follow-up information. The variant rs11614913 CC genotype was associated with a significantly reduced risk of gastric cancer in both sets (adjusted odds ratio [OR]=0.78, 95% confidence interval [CI]=0.62-0.99 for the test set and 0.64, 0.52-0.80 for the validation set) compared with the CT/TT genotypes. Furthermore, the CC genotype was associated with a significantly increased survival of gastric cancer compared with the CT/TT genotypes (adjusted hazard ratio [HR]=0.72, 95% CI=0.55-0.95), and the association was more prominent among patients with non-cardia gastric cancer than those with cardia gastric cancer (adjusted HR=0.57, 95% CI=0.40-0.83 for NCGC and 1.00, 0.65-1.53 for CGC). Our results suggested that the genetic variation of MIR196A2 may play a role in gastric cancer tumorigenesis. © 2013 Wiley Periodicals, Inc.
Chen L.-J.,Soochow University of China |
Zheng X.,Soochow University of China |
Shen Y.-P.,Soochow University of China |
Zhu Y.-B.,Soochow University of China |
And 8 more authors.
Cancer Immunology, Immunotherapy | Year: 2013
In the present study, we studied the expression of T-bet, a key marker for type 1 immune responses, within the tumor microenvironment of gastric cancer, and analyzed its association with clinicopathological parameters. One hundred and fifty-two archival paraffin-embedded gastric tumor tissues were collected, and the expression of T-bet in these cancer tissue specimens was examined by immunohistochemistry. T-bet+ tumor-infiltrating lymphocytes (TILs) in some gastric cancer tissues were further characterized by flow cytometric analysis. The density of T-bet+ TILs in gastric cancer tissues in relation to patient's clinicopathological parameters and postoperative prognosis has been analyzed. Herein, we have found significant increases in T-bet + lymphocytes in tumor tissues as compared with normal stomach tissues, gastritis tissues or gastric polyp specimens. T-bet+ cells mainly consisted of CD4+, CD8+ and CD56+ TILs. In addition, lower numbers of T-bet+ TILs were associated with poor clinicopathological parameters such as invasion to muscular layer, larger tumor size and advanced cancer stages. Moreover, patients with higher numbers of T-bet+ TILs have longer disease-free survival and overall survival. Thus, our study supports the idea that tumor growth elicits spontaneous type 1 cellular immune responses and tumor progression is associated with suppression of antitumor immunity. T-bet expression within tumor can serve as a prognostic indicator for gastric cancer and a potential biomarker for immunotherapy. © 2012 Springer-Verlag Berlin Heidelberg.
PubMed | Nanjing Medical University, Aoyang Hospital and Yixing Tumor Hospital
Type: Journal Article | Journal: Mutagenesis | Year: 2016
The long non-coding RNA (lncRNA) H19 as an imprinted gene transcribed from only the maternal allele has the vital role in carcinogenesis. Aberrant H19 expression is involved in bladder cancer development. In this study, we explored the association between single nucleotide polymorphisms (SNPs) in H19 and bladder cancer risk. Four tagging SNPs (tagSNPs) were selected from the 1000 Genomes Project database. In total, 1049 bladder cancer cases and 1399 controls were recruited in this case-control study. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated by using unconditional univariate and multivariate logistic regression models to evaluate associations between the H19 tagSNPs genotypes and risk of bladder cancer. We found a statistically significant increased risk of bladder cancer in the carriers of the rs217727 AA genotype compared with carriers of GG/GA genotype (OR = 1.31, 95% CI = 1.03-1.67). The subsequently stratified analyses also revealed that the H19 rs217727 AA genotype remarkably elevated the risk of bladder cancer in subgroups of young subjects (OR = 1.80, 95% CI = 1.16-2.81), males (OR = 1.44, 95% CI = 1.10-1.89) and smokers (OR = 1.55, 95% CI = 1.06-2.27), as well as high tumour grade (OR = 1.89, 95% CI = 1.23-2.91) and invasive disease (OR = 1.62, 95% CI = 1.01-2.60). This finding indicates that the rs217727 polymorphism is significantly associated with the risk of bladder cancer.
PubMed | Yixing Tumor Hospital and Nanjing Medical University
Type: Journal Article | Journal: Journal of X-ray science and technology | Year: 2016
Radiation therapy is a typical treatment for esophageal squamous cell carcinoma (ESCC), especially middle and upper segment esophagus, and inoperable patients. However, how to promote radiation sensitivity in radio-resistant cancer cells is a conundrum. Here, our study investigated the radiosensitizing effect of bortezomib, a specific and reversible dipeptide boronic acid analog, in ESCC cells. Human esophageal squamous carcinoma cell lines Eca109 and TE-13 were exposed to hypoxia and/or ionizing radiation (IR) with or without treatment of bortezomib. Cell proliferation assay was performed with CCK8. Cell apoptosis and cell cycle assay were performed with flow cytometry. The radiosensitization effect of was assessed by clonogenic survival and progression of tumor xenograft. The expression of HIF-1, VEGF, and apoptosis proteins was evaluated by Western blot. Radiation-induced DNA double strand break and homologous recombination repair were assessed by immunofluorescence. Our results show that bortezomib efficiently radiosensitizes ESCC cells by decreasing the expression of HIF- 1 and VEGF, inducing apoptosis by activating caspase, and delaying DNA damage repair after radiation.
PubMed | Yixing Tumor Hospital, Nanjing Medical University and Shanxi Peoples Hospital
Type: Journal Article | Journal: PloS one | Year: 2014
Genome-wide association studies (GWAS) have demonstrated that the single nucleotide polymorphism (SNP) MAP3K1 rs889312 is a genetic susceptibility marker significantly associated with a risk of hormone-related tumors such as breast cancer. Considering steroid hormone-mediated signaling pathways have an important role in the progression of gastric cancer, we hypothesized that MAP3K1 rs889312 may be associated with survival outcomes in gastric cancer. The purpose of this study was to test this hypothesis.We genotyped MAP3K1 rs889312 using TaqMan in 884 gastric cancer patients who received subtotal or total gastrectomy. Kaplan-Meier survival analysis and Cox proportional hazard regression were used to analyze the association between MAP3K1 rs889312 genotypes and survival outcomes of gastric cancer.Our findings reveal that the rs889312 heterozygous AC genotype was significantly associated with an increased rate of mortality among patients with diffuse-type gastric cancer (log-rank P=0.028 for AC versus AA/CC, hazard ratio [HR]=1.32, 95% confidence interval [CI]=1.03-1.69), compared to those carrying the homozygous variant genotypes (AA/CC). Additionally, univariate and multivariate Cox regression analysis demonstrate that rs889312 polymorphism was an independent risk factor for poor survival in these patients.In conclusion, we demonstrate that MAP3K1 rs889312 is closely correlated with outcome among diffuse-type gastric cancer. This raises the possibility for rs889312 polymorphisms to be used as an independent indicator for predicting the prognosis of diffuse-type gastric cancer within the Chinese population.
PubMed | Nanjing Medical University, Yixing Tumor Hospital and Yixing Peoples Hospital
Type: Journal Article | Journal: International journal of molecular sciences | Year: 2014
The orphan nuclear receptor (NR5A2), which belongs to the NR5A subfamily of nuclear receptors, is expressed in developing and adult tissues of endodermal origin, and can contribute to the development of several cancers through regulating cell proliferation. NR5A2 (rs3790843 and rs3790844) single nucleotide polymorphisms (SNPs) genotyping were examined in DNA samples, extracted from paraffin-embedded cancer tissue. Clinicopathologic and follow-up data were collected from 944 patients with gastric cancer (GC). Associations of the 2 SNPs with the progression and prognosis in gastric cancer patients were analyzed using the SPSS version 18.0. We found that NR5A2 rs3790843 polymorphism was significantly associated with the risk of GC which had regional lymph node metastasis (p = 0.044) or distant metastasis (p = 0.020). Our results also indicated that rs3790844 polymorphism was associated with the increased overall survival (OS) of GC patients in the dominant model (GG vs. GA/AA, HR (hazard ratio) = 0.823, 95% CI (confidence interval) = 0.679-0.997), suggesting a potential protective role of the variant A allele. Additionally, in the stratified analysis, both NR5A2 rs3790843 and rs3790844 polymorphism were associated with significantly lower risk of death in the groups of female, tumor size >5 cm in a dominant model. Our results represent the first demonstration that the NR5A2 rs3790844 polymorphism is associated with increased OS of GC patients in the dominant model, and similar results were found among the female group and tumor size >5 cm group for NR5A2 rs3790843 polymorphism. Further validation in other larger studies with different ethnic populations and functional evaluations are needed.