Alternative Splicing Factor Heterogeneous Nuclear Ribonucleoprotein U as a Promising Biomarker for Gastric Cancer Risk and Prognosis with Tumor-Promoting Properties.

Gastric cancer (GC) is a major global health concern with poor outcomes. Heterogeneous nuclear ribonucleoprotein U (HNRNPU) is a multifunctional protein that participates in pre-mRNA packaging, alternative splicing regulation, and chromatin remodeling. Its potential role in GC remains unclear. In this study, the expression characteristics of HNRNPU were analyzed by The Cancer Genome Atlas data, Gene Expression Omnibus data, and then further identified by real-time quantitative PCR and immunohistochemistry using tissue specimens. From superficial gastritis, atrophic gastritis, and hyperplasia to GC, the in situ expression of HNRNPU protein gradually increased, and the areas under the curve for diagnosis of GC and its precancerous lesions were 0.911 and 0.847, respectively. A nomogram integrating HNRNPU expression, lymph node metastasis, and other prognostic indicators exhibited an area under the curve of 0.785 for predicting survival risk. Knockdown of HNRNPU significantly inhibited GC cell proliferation, migration, and invasion and promoted apoptosis in vitro. In addition, RNA-sequencing analysis showed that HNRNPU could affect alternative splicing events in GC cells, with functional enrichment analysis revealing that HNRNPU may exert malignant biological function in GC progression through alternative splicing regulation. In summary, the increased expression of HNRNPU was significantly associated with the development of GC, with a good performance in diagnosing and predicting the prognostic risk of GC. Functionally, HNRNPU may play an oncogenic role in GC by regulating alternative splicing.

Expression profiles and prognostic roles of m6A writers, erasers and readers in gastric cancer.

Aim: To explore the expression profiles of N6-methyladenosine (m6A) enzymes (writers, erasers and readers) and their associations with gastric cancer (GC) prognosis. Methods: Gene expression was analyzed using the UALCAN and Oncomine web resources. The prognostic roles of these genes in GC were analyzed using data from The Cancer Genome Atlas. Results: Thirteen m6A enzymes were found to be upregulated in GC tissues. The expression of m6A writers METTL3, RBM15 and WTAP was associated with pathological stage. The m6A eraser FTO was related to tumor stage and ALKBH5 expression was related to GC prognosis. The m6A reader YTHDF3 expression was associated with tumor stage. YTHDC2 was associated with survival of GC patients. Conclusion: Abnormal changes of key genes involved in m6A RNA methylation may have an important impact on GC development and prognosis.

Lay abstract RNA N6-methyladenosine (m6A) methylation is modulated by a series of epigenetic modulator enzymes termed 'writers', 'erasers' and 'readers'. We aimed to explore the expression profiles of these m6A enzymes and their associations with gastric cancer (GC) development and prognosis. Gene expression was analyzed using the UALCAN and Oncomine web resources. Clinical data were downloaded from The Cancer Genome Atlas. Gene­gene networks and protein­protein interaction networks were built using the softwares STRING and GeneMANIA. Thirteen m6A enzymes were found to be upregulated in GC tissues. The expression of m6A writers METTL3, RBM15 and WTAP was associated with pathological stage. The m6A eraser FTO was related to tumor stage and ALKBH5 expression was related to GC prognosis. The m6A reader YTHDF3 expression was associated with tumor stage, and YTHDC2 was associated with survival of GC patients. In summary, these results suggest that abnormal changes of key genes involved in regulation and function of m6A RNA methylation may have an important impact on GC development and its clinical prognosis.

The expression patterns and the diagnostic/prognostic roles of PTPN family members in digestive tract cancers.

BACKGROUND: Non-receptor protein tyrosine phosphatases (PTPNs) are a set of enzymes involved in the tyrosyl phosphorylation. The present study intended to clarify the associations between the expression patterns of PTPN family members, and diagnosis as well as the prognosis of digestive tract cancers. METHODS: Oncomine and Ualcan were used to analyze PTPN expressions. Data from The Cancer Genome Atlas (TCGA) were downloaded through UCSC Xena for validation and to explore the relationship of the PTPN expression with diagnosis, clinicopathological parameters and survival of digestive tract cancers. Gene ontology enrichment analysis was conducted using the DAVID database. The gene-gene interaction network was performed by GeneMANIA and the protein-protein interaction (PPI) network was built using STRING portal coupled with Cytoscape. The expression of differentially expressed PTPNs in cancer cell lines were explored using CCLE. Moreover, by histological verification, the expression of four PTPNs in digestive tract cancers were further analyzed. RESULTS: Most PTPN family members were associated with digestive tract cancers according to Oncomine, Ualcan and TCGA data. Several PTPN members were differentially expressed in digestive tract cancers. For esophageal carcinoma (ESCA), PTPN1 and PTPN12 levels were correlated with incidence; PTPN20 was associated with poor prognosis. For stomach adenocarcinoma (STAD), PTPN2 and PTPN12 levels were correlated with incidence; PTPN3, PTPN5, PTPN7, PTPN11, PTPN13, PTPN14, PTPN18 and PTPN23 were correlated with pathological grade; PTPN20 expression was related with both TNM stage and N stage; PTPN22 was associated with T stage and pathological grade; decreased expression of PTPN5 and PTPN13 implied worse overall survival of STAD, while elevated PTPN6 expression indicated better prognosis. For colorectal cancer (CRC), PTPN2, PTPN21 and PTPN22 levels were correlated with incidence; expression of PTPN5, PTPN12, and PTPN14 was correlated with TNM stage and N stage; high PTPN5 or PTPN7 expression was associated with increased hazards of death. CCLE analyses showed that in esophagus cancer cell lines, PTPN1, PTPN4 and PTPN12 were highly expressed; in gastric cancer cell lines, PTPN2 and PTPN12 were highly expressed; in colorectal cancer cell lines, PTPN12 was highly expressed while PTPN22 was downregulated. Results of histological verification experiment showed differential expressions of PTPN22 in CRC, and PTPN12 in GC and CRC. CONCLUSIONS: Members of PTPN family were differentially expressed in digestive tract cancers. Correlations were found between PTPN genes and clinicopathological parameters of patients. Expression of PTPN12 was upregulated in both STAD and CRC, and thus could be used as a diagnostic biomarker. Differential expression of PTPN12 in GC and CRC, and PTPN22 in CRC were presented in our histological verification experiment.

Aberrantly methylated-differentially expressed genes and pathways in Epstein-Barr virus-associated gastric cancer.

Aim: To identify the methylated-differentially expressed genes (MDEGs) that may serve as diagnostic markers and therapeutic targets in Epstein-Barr virus-associated gastric cancer (EBVaGC) and to explore the methylation-based pathways for elucidating biological mechanisms of EBVaGC. Materials & methods: Gene expression and methylation profiles were downloaded from GEO database. MDEGs were identified by GEO2R. Pathway enrichment analyses were conducted based on DAVID database. Hub genes were identified by Cytoscape, which were further verified by The Cancer Genome Atlas database. Results: A total of 367 hypermethylated, lowly expressed genes were enriched in specific patterns of cell differentiation. 31 hypomethylated, highly expressed genes demonstrated enrichment in regulation of immune system process. After validation using The Cancer Genome Atlas database, seven genes were confirmed to be significantly different hub genes in EBVaGC. Conclusion: EBVaGC-specific MDEGs and pathways can be served as potential biomarkers for precise diagnosis and treatment of EBVaGC and provide novel insights into the mechanisms involved.

Key elements involved in Epstein-Barr virus-associated gastric cancer and their network regulation.

BACKGROUND: The molecular mechanism of Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) remains elusive. A collection of molecular regulators including transcription factor and noncoding RNA (ncRNAs) may affect the carcinogenesis of EBVaGC by regulating the expression and function of key genes. In this study, integration of multi-level expression data and bioinformatics approach was used to identify key elements and their interactions involved in mechanism of EBVaGC and their network regulation. METHODS: Data of the gene expression profiling data sets (GSE51575) was downloaded from GEO database. Differentially expressed genes between EBVaGC and normal samples were identified by GEO2R. Gene ontology and pathway enrichment analyses were performed using R packages Cluster profiler. STRING database was used to find interacting proteins between different genes. Transcription factors in differentially expressed genes were obtained from TF Checkpoint database. Using Cytoscape, we built transcription factor regulation network. miRNAs involved in the gene-interacting proteins and the miRNA-targeted lncRNA were predicted through miRWalk. Using ViRBase, EBV related miRNA regulation network was built. Overlapping genes and regulators of the above three networks were further identified, and the cross network was constructed using Cytoscape software. Moreover, the differential expressions of the target genes and transcription factors in the cross network were explored in different molecular subtypes of GC using cBioPortal. By histological verification, the expression of two main target genes in the cross network were further analyzed. RESULTS: A total of 104 genes showed differential expressions between EBVaGC and normal tissues, which were associated with digestion, G-protein coupled receptor binding, gastric acid secretion, etc. Pathway analysis showed that the differentially expressed genes were mainly enriched in gastric acid secretion and protein digestion and absorption. Using STRING dataset, a total of 54 proteins interacted with each other. Based on the transcription factor network, the hub transcription factors IRX3, NKX6-2, PTGER3 and SMAD5 were identified to regulate their target genes SST and GDF5, etc. After screening and matching in miRwalk datasets, a ceRNA network was established, in which the top five miRNAs were hsa-miR-4446-3p, hsa-miR-5787, hsa-miR-1915-3p, hsa-miR-335-3p and hsa-miR-6877-3p, and the top two lncRNAs were RP5-1039K5.19 and TP73-AS1. According to the EBV related miRNA regulation network, CXCL10 and SMAD5 were found to be regulated by EBV-miR-BART1-3p and EBV-mir-BART22, respectively. By overlapping the three networks, CXCL10, GDF5, PTGER3, SMAD5, miR-6877-3p, RP5-1039K5.19, TP73-AS1, EBV-miR-BART1-3p and EBV-mir-BART22 were found to be key elements of regulation mechanism of EBVaGC. CXCL10, GDF5, PTGER3 and SMAD5 were also differentially expressed among the four molecular subtypes of GC. The histological verification experiment showed differential expressions of the two main target genes GDF5 and CXCL10 between EBVaGC and non-tumor tissues as well as EBVnGC. CONCLUSION: In the current study, our results revealed key elements and their interactions involved in EBVaGC. Some hub transcription factors, miRNAs, lncRNAs and EBV related miRNAs were observed to regulate their target genes. Overlapping genes and regulators were observed in diverse regulation networks, such as CXCL10, GDF5, PTGER3, SMAD5, miR-6877-3p, RP5-1039K5.19, TP73-AS1, EBV-miR-BART1-3p and EBV-mir-BART22. Moreover, CXCL10, GDF5, PTGER3 and SMAD5 were also differentially expressed among the four molecular subtypes of GC. The histological verification experiment showed differential expressions of the two main target genes GDF5 and CXCL10 between EBVaGC and non-tumor tissues as well as EBVnGC. Therefore, the identified key elements and their network regulation may be specifically involved in EBVaGC mechanisms.

Serum levels of matrix metalloproteinase 9 and toll-like receptor 4 in acute aortic dissection: a case-control study.

BACKGROUND: Matrix metalloproteinase 9 (MMP9) and Toll-like receptor 4 (TLR4) play important roles in aortic pathophysiology. However, there is lacking research on serum TLR4 levels in acute aortic dissection (AAD) patients, and the performance of serum MMP9 and TLR4 for the diagnosis of AAD is still unknown. This study aimed to evaluate the serum levels of MMP9 and TLR4 in AAD patients, identify their associations with circulating C-reactive protein (CRP) and D-dimer, which are well-known classical biomarkers of AAD, and further explore the potential diagnostic role of MMP9 and TLR4 in AAD. METHODS: Serum levels of MMP9 and TLR4 were measured by enzyme-linked immunosorbent assay (ELISA) in 88 AAD patients and 88 controls. The clinical test related information was collected from patients' electronic medical records. RESULTS: Serum MMP9 and TLR4 levels were significantly higher in AAD patients than those in healthy controls in the general and stratified comparisons. Either serum MMP9 or TLR4 was independently associated with the risk of AAD (all p < 0.001). There was a positive significant association between serum MMP9 and TLR4 (r = 0.518, p < 0.001). Both MMP9 and TLR4 levels were statistically correlated with circulating CRP, but not D-dimer. Based on receiver-operating characteristic (ROC) analysis, the area under the curves (AUCs) of MMP9 and TLR4 alone for the diagnosis of AAD were 0.810 and 0.799 with optimal cut-off points of 379.47 ng/ml and 7.83 ng/ml, respectively. Moreover, a combination of serum MMP9 and TLR4 increased the AUC to 0.89 with a sensitivity of 60.2% and specificity of 94.3%. CONCLUSIONS: Serum MMP9 and TLR4 could be potential biomarkers for identifying AAD, while the combined diagnostic value was higher in safely ruling out AAD.

Serum matrix metalloproteinase-9 is a valuable biomarker for identification of abdominal and thoracic aortic aneurysm: a case-control study.

BACKGROUND: Matrix metalloproteinase-9 (MMP9) has been reported to play a key role in the pathogenesis of aortic aneurysm. However, few studies have assessed serum MMP9 levels in both abdominal aortic aneurysm (AAA) and thoracic aortic aneurysm (TAA). In this study, we investigated the serum levels of MMP9 in aortic aneurysm to evaluate its predictive and diagnostic efficacy for AAA and TAA, and explored the association of MMP9 with circulating laboratory markers. METHODS: A total of 296 subjects were enrolled, including 105 AAA patients, 79 TAA patients and 112 healthy controls. The levels of serum MMP9 were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared to control group, both AAA and TAA patients had higher serum MMP9 levels in the overall comparison and subgroup analysis based on subjects aged<65 years, either male or female, hypertension, non-diabetes and non-hyperlipidemia (all P<0.05). Moreover, MMP9 levels were significantly higher in TAA group than those in AAA group in the total comparison, and this discrepancy was also found in the non-diabetes, non-hyperlipidemia and aortic diameter ≥ 5.5 cm subgroup analysis. Serum MMP9 levels were influenced by age and hypertension. There was a positive association of serum MMP9 with CRP (r = 0.33, P < 0.001) and Hcy (r = 0.199, P = 0.033). Multiple logistic analyses showed that serum MMP9 was an independent risk factor for AAA and TAA. Based on receiver operating characteristic (ROC) analysis, the area under the curve (AUC) of MMP9 for predicting TAA was 0.83 with 70% sensitivity and 91% specificity, while the AUC of MMP9 to detect AAA was 0.69 and the sensitivity and specificity were 50% and 88%. CONCLUSIONS: Serum MMP9 was closely related to the existence of aortic aneurysms and could be a valuable marker for the discrimination of aortic aneurysm, especially for TAA.

Effect of ERCC8 tagSNPs and their association with H. pylori infection, smoking, and alcohol consumption on gastric cancer and atrophic gastritis risk.

Excision repair cross-complementing group 8 (ERCC8) plays a critical role in DNA repair. Genetic polymorphisms in ERCC8 may contribute to the risk of cancer development. We selected tag single nucleotide polymorphisms (tagSNPs) in Chinese patients from the HapMap database to investigate associations with gastric cancer and its precursors. Genomic DNA was extracted from 394 controls, 394 atrophic gastritis, and 394 gastric cancer cases in northern Chinese patients, and genotypes were identified using the Sequenom MassARRAY system. We found that the ERCC8 rs158572 GG+GA genotype showed a 1.651-fold (95 % confidence interval (CI) = 1.109-2.457, P = 0.013) increased risk of gastric cancer compared with the AA genotype, especially in diffuse type. Stratified analysis comparing the common genotype revealed significantly increased gastric cancer risk in males and individuals older than 50 years with rs158572 GA/GG/GG+GA genotypes, while individuals older than 50 years with rs158916 CT/CC+CT genotypes were less susceptible to atrophic gastritis. Haplotype analysis showed that the G-T haplotype was associated with increased risk of gastric cancer. Statistically significant interactions between the two ERCC8 tagSNPs and Helicobacter pylori infection were observed for gastric cancer and atrophic gastritis risk (P < 0.05). Smokers and drinkers with ERCC8 rs158572 GG+GA genotype were more susceptible to gastric cancer compared with non-smokers and non-drinkers homozygous for AA. Our findings suggested that ERCC8 rs158572 and rs158916, alone or together with environmental factors, might be associated with gastric cancer and atrophic gastritis susceptibility. Further validation of our results in larger populations along with additional studies evaluating the underlying molecular function is required.

Single nucleotide polymorphisms of whole genes and atrophic gastritis susceptibility:a systematic review and meta-analysis.

BACKGROUND: Atrophic gastritis (AG) is one of the important precancerous lesions of gastric cancer. Single nucleotide polymorphisms (SNPs) are closely related to AG susceptibility. However, the research conclusions on the predictive potential of SNPs are inconsistent. The study aims to retrospect the association between SNPs of whole genes and AG risk by meta-analysis. MATERIALS AND METHODS: Up to April 29, 2020, a systematic literature search for the relationship of SNPs with AG susceptibility was performed utilizing PubMed, Web of Science and Chinese National Knowledge Infrastructure. The overall and stratified meta-analyses on extracted data were conducted by Stata11.2. RESULTS: 33 case-control studies were enrolled containing 9951 AG patients and 17,252 healthy controls, and 17 SNPs in 12 different genes were systematically reviewed. The results indicated that 12 genes could be categorized based on their functions, including immune response, cell proliferation and apoptosis, and DNA damage repair. For the SNPs in immune response-related genes, the C allele of TLR1 rs4833095 T/C increased AG risk to 1.21-fold and the recessive model of TLR4 rs11536878 in the TLR gene family decreased AG susceptibility to 0.48-fold. The variant alleles of IL-10 rs1800871 (OR = 1.21) and IL-8 rs4073 (OR = 1.22) in the IL gene family were positively associated with AG risk. PSCA rs2294008 enhanced AG risk in all genetic models. SNPs associated with AG susceptibility were mainly focused on immune response-related genes. CONCLUSION: These SNPs related to immune response could influence on AG risk and have potential to be AG predictive biomarkers. It is worth noting that the number of studies for each SNPs were insufficient due to the limited published researches and updated meta-analysis needs to be performed based on extensive relevant studies for more reliable results.

Nucleotide excision repair pathway gene polymorphisms are associated with risk and prognosis of colorectal cancer.

BACKGROUND: Single nucleotide polymorphisms (SNPs) are universally present in nucleotide excision repair (NER) pathway genes, which could make impacts on colorectal carcinogenesis and prognosis. AIM: To explore the association of all tagSNPs in NER pathway genes with colorectal cancer (CRC) risk and prognosis in a northern Chinese population by a two-stage case-control design composed of a discovery and validation stage. METHODS: Genotyping for NER SNPs was performed using kompetitive allele specific PCR. In the discovery stage, 39 tagSNPs in eight genes were genotyped in 368 subjects, including 184 CRC cases and 184 individual-matched controls. In the validation stage, 13 SNPs in six genes were analyzed in a total of 1712 subjects, including 854 CRC cases and 858 CRC-free controls. RESULTS: Two SNPs (XPA rs10817938 and XPC rs2607775) were associated with an increased CRC risk in overall and stratification analyses. Significant cumulative and interaction effects were also demonstrated in the studied SNPs on CRC risk. Another two SNPs (ERCC2 rs1052555 and ERCC5 rs2228959) were newly found to be associated with a poor overall survival of CRC patients. CONCLUSION: Our findings suggest novel SNPs in NER pathway genes that can be predictive for CRC risk and prognosis in a large-scale Chinese population. The present study has referential values for the identification of all-round NER-based genetic biomarkers in predicting the susceptibility and clinical outcome of CRC.

Association of IL10 gene promoter polymorphisms with risks of gastric cancer and atrophic gastritis.

OBJECTIVE: To investigate the association between polymorphisms of the interleukin 10 ( IL10) gene and risk of gastric cancer (GC) and atrophic gastritis (AG). METHODS: This study enrolled patients with GC, patients with AG and healthy control subjects. Demographic data were collected and the IL10 gene -1082A/G, -819C/T and -592A/C polymorphisms were genotyped. An enzyme-linked immunosorbent assay was performed to detect Helicobacter pylori infection. RESULTS: The study enrolled 556 participants including 208 in the GC group, 116 in the AG group and 232 controls (CON group). In a recessive model of the IL10-819C/T polymorphism, a significantly decreased risk of GC was found compared with AG and non-cancer subjects, respectively (AG→GC: odds ratio OR 0.41; non-cancer→GC: OR 0.57). The CC genotype demonstrated a significantly increased risk of AG compared with CON. Similar significant results were detected in males and H. pylori-negative subgroups. The ACC haplotype was associated with a decreased risk of GC compared with AG. The ATC haplotype was associated with a decreased risk of AG compared with the CON group, but it was associated with an increased risk of GC compared with AG. CONCLUSION: The IL10 gene promoter -819C/T (rs1800871) polymorphism was associated with the risk of GC and AG in a Chinese population.

Serum Toll-like receptor 4: A novel and promising biomarker for identification of aortic aneurysmal diseases.

BACKGROUND: Immune inflammation appears to play a role in aortic aneurysm (AA) pathology. Toll-like receptor 4 (TLR4) has been proved to involve in immune inflammatory diseases. However, the relationship between serum TLR4 and AA is still unclear. METHODS: The study included 282 AA patients and 287 controls. The clinical test related information was collected in medical records. The levels of serum TLR4 were measured by enzyme-linked immunosorbent assay. RESULTS: Serum TLR4 levels were significantly higher in case groups and could be influenced by age, smoking, hypertension, diabetes and hyperlipidemia. Serum TLR4 was positively correlated with circulating CRP, Hcy, D-dimer, Fg and Cys-c in AA patients, even after adjusting the possible influencing factors. The optimal cut-off value of TLR4 was 13.64 ng/ml for discriminating AA, and the screening accuracy was higher for those who were males (sensitivity of 63.5% and specificity of 68.6%), smokers (sensitivity of 63.5% and specificity of 82.7%) and hyperlipidemia (sensitivity of 59.1% and specificity of 81.2%). Multiple logistic analyses showed that serum TLR4 was significantly correlated with AA risk (OR = 1.119, 95% CI = 1.077-1.162, p < 0.001) and subjects with high TLR4 levels (>13.64 ng/ml) were more likely to have AA (OR = 4.225, 95% CI = 2.477-7.206, p < 0.001). CONCLUSIONS: Serum TLR4 was closely related to AA and associated with some AA-related circulating markers. Serum TLR4 could be a novel and promising biomarker with important diagnostic and predictive value in the identification of aortic aneurysmal diseases.

Epistatic SNP interaction of ERCC6 with ERCC8 and their joint protein expression contribute to gastric cancer/atrophic gastritis risk.

Excision repair cross-complementing group 6 and 8 (ERCC6 and ERCC8) are two indispensable genes for the initiation of transcription-coupled nucleotide excision repair pathway. This study aimed to evaluate the interactions between single nucleotide polymorphisms of ERCC6 (rs1917799) and ERCC8 (rs158572 and rs158916) in gastric cancer and its precancerous diseases. Besides, protein level analysis were performed to compare ERCC6 and ERCC8 expression in different stages of gastric diseases, and to correlate SNPs jointly with gene expression. Sequenom MassARRAY platform method was used to detect polymorphisms of ERCC6 and ERCC8 in 1916 subjects. In situ ERCC6 and ERCC8 protein expression were detected by immunohistochemistry in 109 chronic superficial gastritis, 109 chronic atrophic gastritis and 109 gastric cancer cases. Our results demonstrated pairwise epistatic interactions between ERCC6 and ERCC8 SNPs that ERCC6 rs1917799-ERCC8 rs158572 combination was associated with decreased risk of chronic atrophic gastritis and increased risk of gastric cancer. ERCC6 rs1917799 also showed a significant interaction with ERCC8 rs158916 to reduce gastric cancer risk. The expressions of ERCC6, ERCC8 and ERCC6-ERCC8 combination have similarities that higher positivity was observed in chronic superficial gastritis compared with chronic atrophic gastritis and gastric cancer. As for the effects of ERCC6 and ERCC8 SNPs on the protein expression, single SNP had no correlation with corresponding gene expression, whereas the ERCC6 rs1917799-ERCC8 rs158572 pair had significant influence on ERCC6 and ERCC6-ERCC8 expression. In conclusion, ERCC6 rs1917799, ERCC8 rs158572 and rs158916 demonstrated pairwise epistatic interactions to associate with chronic atrophic gastritis and gastric cancer risk. The ERCC6 rs1917799-ERCC8 rs158572 pair significantly influence ERCC6 and ERCC6-ERCC8 expression.

The interaction effects of pri-let-7a-1 rs10739971 with PGC and ERCC6 gene polymorphisms in gastric cancer and atrophic gastritis.

BACKGROUND: The aim of this study was to investigate the interaction effects of pri-let-7a-1 rs10739971 with pepsinogen C (PGC) and excision repair cross complementing group 6 (ERCC6) gene polymorphisms and its association with the risks of gastric cancer and atrophic gastritis. We hoped to identify miRNA polymorphism or a combination of several polymorphisms that could serve as biomarkers for predicting the risk of gastric cancer and its precancerous diseases. METHODS: Sequenom MassARRAY platform method was used to detect polymorphisms of pri-let-7a-1 rs10739971 G → A, PGC rs4711690 C → G, PGC rs6458238 G → A, PGC rs9471643 G → C, and ERCC6 rs1917799 in 471 gastric cancer patients, 645 atrophic gastritis patients and 717 controls. RESULTS: An interaction effect of pri-let-7a-1 rs10739971 polymorphism with ERCC6 rs1917799 polymorphism was observed for the risk of gastric cancer (P interaction = 0.026); and interaction effects of pri-let-7a-1 rs10739971 polymorphism with PGC rs6458238 polymorphism (P interaction = 0.012) and PGC rs9471643 polymorphism (P interaction = 0.039) were observed for the risk of atrophic gastritis. CONCLUSION: The combination of pri-let-7a-1 rs10739971 polymorphism and ERCC6 and PGC polymorphisms could provide a greater prediction potential than a single polymorphism on its own. Large-scale studies and molecular mechanism research are needed to confirm our findings.

Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms in cancer: a meta-analysis.

Toll-like receptor 4 (TLR4) is critical in the recognition of Gram-negative bacteria serving as a key immune system effector. Recently, a number of case-control studies were conducted to investigate the association between TLR4 gene polymorphism and cancer risk, especially Asp299Gly and Thr399Ile polymorphisms. However, published data were still conflicting. In this paper, we summarized 9463 cancer cases and 10,825 controls from 22 studies and attempted to assess the susceptibility of TLR4 gene polymorphism to cancers by a synthetical meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the relationship. Our results suggested that Asp299Gly represented a risk factor on cancers in digestive system (G allele versus A allele, OR=1.64, 95% CI: 1.02-2.64; GA+GG versus AA, OR=1.64, 95% CI: 1.00-2.71) but tend to have a protective effect on prostate cancer (GG versus AA, OR=0.37, 95% CI: 0.14-0.98; GG versus GA+AA, OR=0.37, 95% CI: 0.14-0.98). Thr399Ile polymorphism was significantly associated with an elevated cancer risk in overall analysis (T allele versus C allele, OR=1.72, 95% CI: 1.27-2.33; TC versus CC, OR=1.63, 95% CI: 1.18-2.26; TT+TC versus CC, OR=1.70, 95% CI: 1.24-2.34) and especially in gastrointestinal subgroup (T allele versus C allele, OR=2.01, 95% CI: 1.40-2.89; TC versus CC, OR=1.86, 95% CI: 1.26-2.74; TT+TC versus CC, OR=1.97, 95% CI: 1.35-2.88). Further prospective researches with larger numbers of worldwide participants are warranted to draw comprehensive and true conclusions.

Gastric cancer incidence and mortality in Zhuanghe, China, between 2005 and 2010.

AIM: To investigate the incidence and mortality of gastric cancer (GC) in Zhuanghe region, northeast China and the influencing factors for their changing trends. METHODS: All new cancer cases and deaths registered from 2005 to 2010 in Zhuanghe County were reviewed. The annual GC cases, constituent ratio, crude rates, age-standardized rates, their sex and age distribution and temporal trends were assessed. The method of annual percentage change (APC) was used to estimate the trends of GC. RESULTS: Altogether 2634 new cases of GC and 1722 related deaths were registered, which accounted for 21.04% and 19.13% of all cancer-related incidence and deaths, respectively. The age-standardized incidence rate steadily decreased from 57.48 in 2005 to 44.53 in 2010 per 10(5) males, and from 18.13 to 14.70 per 10(5) females, resulting in a APC of -5.81% for males and -2.89% for females over the entire period. The magnitude of APC in GC mortality amounted to -11.09% and -15.23%, respectively, as the age-standardized mortality rate steadily decreased from 42.08 in 2005 to 23.71 in 2010 per 10(5) males, and from 23.86 to 10.78 per 10(5) females. Females had a significantly lower incidence (a male/female ratio 2.80, P < 0.001) and mortality (a male/female ratio 2.30, P < 0.001). In both genders, the peak incidence and mortality occurred in the 80-84 years age group. The age-standardized mortality/incidence ratio also decreased from the peak of 0.73 in 2005 to 0.53 in 2010 for males, and from 1.32 to 0.73 for females. CONCLUSION: Encouraging declines of incidence and mortality of GC were observed in Zhuanghe region between 2005 and 2010, possibly due to the economic development and efficient GC control strategies.

Changes in biological and virulent characteristics of Helicobacter pylori exposed to high salt.

The effect of high salt environments on biological characteristics of Helicobacter pylori is still unclear. In the present study, we therefore investigated biological characteristics of the bacterium exposed to high salt concentrations. H. pylori strain, L301, was cultured in media supplemented with different concentrations (3%, 15% and 30%) of sodium chloride (NaCl) under microaerophilic conditions for 48 h. Morphology was assessed by light microscopy, the ATP content was quantitated by single-tube fluorescent light-emission and the levels of CagA and UreB proteins were determined by Western blotting. After exposure to NaCl, H. pylori transformed from common spiral shape to U or even coccoid shapes. The ATP content was significantly higher in 30% NaCl group than in 15% and 3% NaCl group and the level of CagA protein increased with the salt concentration. The urease reaction was all strongly positive in H. pylori exposed to different salt concentrations. The level of 8-OHdG expression was significantly increased in GES-1 cells co-cultured with H. pylori exposed to high salt, compared with the level in uninfected cells. H. pylori survives under exposure to high salt concentrations up to 30%, exhibiting changes in mobility, morphology and CagA expression, associated with increased 8-OHdG in the gastric epithelial cells, indicative of DNA damage.