Dataset Information

Association Between 12 Polymorphisms of VEGF/Hypoxia/Angiogenesis Pathway Genes and Risk of Urogenital Carcinomas: A Meta-Analysis Based on Case-Control Studies.

ABSTRACT: Objective: Previous studies indicated potential associations between polymorphisms in genes of VEGF/hypoxia/angiogenesis pathway and risk of urogenital carcinomas However, the results were controversial and inconclusive. Here, we conducted an in-depth meta-analysis to investigate the precise associations between polymorphisms in VEGF/hypoxia/angiogenesis related genes and risk of urogenital carcinomas. Methods: We searched PubMed, Web of Science, EMBASE, and Cochrane Library to identify all eligible publications. Pooled odds ratios (ORs) corresponding with the 95% confidence intervals (CIs) were calculated to evaluate their associations. Subgroup analysis was conducted to further ascertain such relationship and investigate sources of heterogeneity. Results: In the end, a total of 96 case-control studies fulfilled the inclusion criteria were enrolled for 12 polymorphisms in 4 VEGF/hypoxia/angiogenesis related genes. The pooled results showed eNOS-rs2070744 polymorphism conferred a significantly increased overall risk of urogenital carcinomas in allele, homozygote, and recessive models, respectively. In addition, eNOS-Intron 4a/b VNTR polymorphism was identified related to an increased risk of urogenital carcinomas in recessive model. And VEGF-rs699947 polymorphism was also identified an increased risk of renal cell carcinoma (RCC) in allelic, heterozygote, dominant, homozygote, and recessive models. Conclusion: To conclude, eNOS-rs2070744 and eNOS-Intron 4a/b VNTR polymorphisms are risk factors for urogenital carcinomas. VEGF-rs699947 polymorphism was also identified as an increased risk factor for renal carcinoma.

SUBMITTER: Chen JB

PROVIDER: S-EPMC6004409 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Association Between 12 Polymorphisms of VEGF/Hypoxia/Angiogenesis Pathway Genes and Risk of Urogenital Carcinomas: A Meta-Analysis Based on Case-Control Studies.

Chen Jin-Bo JB Zhang Meng M Cui Yu Y Liu Pei-Hua PH Qi Yan-Wei YW Li Chao C Cheng Xu X Ren Wen-Biao WB Li Qia-Qia QQ Liu Long-Fei LF Chen Min-Feng MF Chen He-Qun HQ Zu Xiong-Bing XB

Frontiers in physiology 20180611

<b>Objective:</b> Previous studies indicated potential associations between polymorphisms in genes of VEGF/hypoxia/angiogenesis pathway and risk of urogenital carcinomas However, the results were controversial and inconclusive. Here, we conducted an in-depth meta-analysis to investigate the precise associations between polymorphisms in VEGF/hypoxia/angiogenesis related genes and risk of urogenital carcinomas. <b>Methods:</b> We searched PubMed, Web of Science, EMBASE, and Cochrane Library to ide ...[more]

PMID: 29942264

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Project description:BackgroundSpalt-like protein 4 (SALL4) is a stemness-related transcription factor whose abnormal re-expression contributes to cancer initiation and progression. However, the role of SALL4 in cancer angiogenesis remains unknown.MethodsAnalyses of clinical specimens via TCGA datasets were performed to determine the expression level and clinical significance of SALL4 in STAD (Stomach Adenocarcinoma). SALL4 knockdown, knockout, and overexpression were achieved by siRNA, CRISPR/Cas9, and plasmid transfection. The effects of conditioned medium (CM) from SALL4 knockdown or overexpression of gastric cancer cells on endothelial cell proliferation, migration, and tube formation were investigated by CCK-8 assay, transwell migration assay, and tube formation assay. The regulation of VEGF gene expression by SALL4 was studied by qRT-PCR, western blot, chromatin immunoprecipitation (ChIP) assay, and electrophoretic mobility shift assay (EMSA). Engineered exosomes from 293T cells loaded with si-SALL4-B and thalidomide were produced to test their therapeutic effect on gastric cancer progression.ResultsSALL4 expression was increased in STAD and positively correlated with tumor progression and poor prognosis. SALL4-B knockdown or knockout decreased while over-expression increased the promotion of human umbilical vein endothelial cells (HUVEC) cell proliferation, migration, and tube formation by gastric cancer cell-derived CM. Further investigation revealed a widespread association of SALL4 with angiogenic gene transcription through the TCGA datasets. Additionally, SALL4-B knockdown reduced, while over-expression enhanced the expression levels of VEGF-A, B, and C genes. The results of ChIP and EMSA assays indicated that SALL4 could directly bind to the promoters of VEGF-A, B, and C genes and activate their transcription, which may be associated with increased histone H3-K79 and H3-K4 modifications in their promoter regions. Furthermore, si-SALL4-B and thalidomide-loaded exosomes could be efficiently uptaken by gastric cancer cells and significantly reduced SALL4-B and Vascular Endothelial Growth Factor (VEGF) expression levels in gastric cancer cells, thus inhibiting the pro-angiogenic role of their derived CM.ConclusionThese findings suggest that SALL4 plays an important role in angiogenesis by transcriptionally regulating VEGF expression. Co-delivery of the functional siRNA and anticancer drug via exosomes represents a useful approach to inhibiting cancer angiogenesis by targeting SALL4/VEGF pathway.

Project description:BACKGROUND:Gastroesophageal reflux disease (GERD), higher body mass index (BMI), smoking, and genetic variants in angiogenic pathway genes have been individually associated with increased risk of esophageal adenocarcinoma. However, how angiogenic gene polymorphisms and environmental factors jointly affect esophageal adenocarcinoma development remains unclear. METHODS:By using a case-only design (n = 335), the authors examined interactions between 141 functional/tagging angiogenic single nucleotide polymorphisms (SNPs) and environmental factors (GERD, BMI, smoking) in modulating esophageal adenocarcinoma risk. Gene-environment interactions were assessed by a 2-step approach. First, the authors applied random forest to screen for important SNPs that had either main or interaction effects. Second, they used case-only logistic regression to assess the effects of gene-environment interactions on esophageal adenocarcinoma risk, adjusting for covariates and false-discovery rate. RESULTS:Random forest analyses identified 3 sets of SNPs (17 SNPs-GERD, 26 SNPs-smoking, and 34 SNPs-BMI) that had the highest importance scores. In subsequent logistic regression analyses, interactions between 2 SNPs (rs2295778 of HIF1AN, rs13337626 of TSC2) and GERD, 2 SNPs (rs2295778 of HIF1AN, rs2296188 of VEGFR1) and smoking, and 7 SNPs (rs2114039 of PDGRFA, rs2296188 of VEGFR1, rs11941492 of VEGFR1, rs17708574 of PDGFRB, rs7324547 of VEGFR1, rs17619601 of VEGFR1, and rs17625898 of VEGFR1) and BMI were significantly associated with esophageal adenocarcinoma development (all false-discovery rates ?0.10). Moreover, these interactions tended to have SNP dose-response effects for increased esophageal adenocarcinoma risk with increasing number of combined risk genotypes. CONCLUSIONS:These findings suggest that genetic variations in angiogenic genes may modify esophageal adenocarcinoma susceptibility through interactions with environmental factors in an SNP dose-response manner.

Dataset Information

Association Between 12 Polymorphisms of VEGF/Hypoxia/Angiogenesis Pathway Genes and Risk of Urogenital Carcinomas: A Meta-Analysis Based on Case-Control Studies.

Publications

Association Between 12 Polymorphisms of VEGF/Hypoxia/Angiogenesis Pathway Genes and Risk of Urogenital Carcinomas: A Meta-Analysis Based on Case-Control Studies.

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