Chronic inflammation due to Helicobacter pylori (H. pylori) infection promotes gastric carcinogenesis. Tumour necrosis factor-α (TNF-α), a key mediator of inflammation, induces cell survival or apoptosis by binding to two receptors (TNFR1 and TNFR2). TNFR1 can induce both survival and apoptosis, while TNFR2 results only in cell survival. The dysregulation of these processes may contribute to carcinogenesis.

To evaluate the effects of TNFR1 and TNFR2 downregulation in AGS cells treated with H. pylori extract on the TNF-α pathway.

AGS cell lines containing TNFR1 and TNFR2 receptors downregulated by specific shRNAs and nonsilenced AGS cells were treated with H. pylori extract for 6 h. Subsequently, quantitative polymerase chain reaction with TaqMan^® assays was used for the relative quantification of the mRNAs (TNFA, TNFR1, TNFR2, TRADD, TRAF2, CFLIP, NFKB1, NFKB2, CASP8, CASP3) and miRNAs (miR-19a, miR-34a, miR-103a, miR-130a, miR-181c) related to the TNF-α signalling pathway. Flow cytometry was employed for cell cycle analysis and apoptosis assays.

In nonsilenced AGS cells, H. pylori extract treatment increased the expression of genes involved in cell survival and inhibited both apoptosis (NFKB1, NFKB2 and CFLIP) and the TNFR1 receptor. TNFR1 downregulation significantly decreased the expression of the TRADD and CFLIP genes, although no change was observed in the cellular process or miRNA expression. In contrast, TNFR2 downregulation decreased the expression of the TRADD and TRAF2 genes, which are both important downstream mediators of the TNFR1-mediated pathway, as well as that of the NFKB1 and CFLIP genes, while upregulating the expression of miR-19a and miR-34a. Consequently, a reduction in the number of cells in the G0/G1 phase and an increase in the number of cells in the S phase were observed, as well as the promotion of early apoptosis.

Our findings mainly highlight the important role of TNFR2 in the TNF-α pathway in gastric cancer, indicating that silencing it can reduce the expression of survival and anti-apoptotic genes.

• Gastric cancer
• Helicobacter pylori
• Tumour necrosis factor-α signalling pathway
• TNFR1
• TNFR2
• miRNAs

• Apoptosis
• Carcinogenesis
• Cell Cycle
• Down-Regulation
• Gene Expression
• Humans
• Inflammation
• MicroRNAs/genetics
• Receptors, Tumor Necrosis Factor, Type I/genetics
• Receptors, Tumor Necrosis Factor, Type I/metabolism
• Receptors, Tumor Necrosis Factor, Type II/genetics
• Stomach Neoplasms/genetics
• TNF Receptor-Associated Death Domain Protein/metabolism
• TNF Receptor-Associated Factor 2/genetics
• TNF Receptor-Associated Factor 2/metabolism
• Tumor Necrosis Factor-alpha/metabolism

Gastric carcinogenesis can be induced by chronic inflammation triggered by Helicobacter pylori (H. pylori) infection. Tumor necrosis factor (TNF)-α and its receptors (TNFR1 and TNFR2) regulate important cellular processes, such as apoptosis and cell survival, and the disruption of which can lead to cancer. This signaling pathway is also modulated by microRNAs (miRNAs), altering gene expression.

To evaluate the mRNA and miRNAs expression involved in the TNF-α signaling pathway in gastric cancer (GC) tissues and its relationship.

Quantitative polymerase chain reaction (qPCR) by TaqMan^® assay was used to quantify the RNA transcript levels of TNF-α signaling pathway (TNF, TNFR1, TNFR2, TRADD, TRAF2, CFLIP, NFKB1, NFKB2, CASP8, CASP3) and miRNAs that targets genes from this pathway (miR-19a, miR-34a, miR-103a, miR-130a, miR-181c) in 30 GC fresh tissue samples. Molecular diagnosis of H. pylori was performed by nested PCR for gene HSP60. A miRNA:mRNA interaction network was construct using Cytoscape v3.1.1 from the in silico analysis performed using public databases.

Up-regulation of cellular survival genes as TNF, TNFR2, TRADD, TRAF2, CFLIP, and NFKB2, besides CASP8 and miR-34a was observed in GC tissues, whereas mediators of apoptosis such as TNFR1 and CASP3 were down-regulated. When the samples were stratified by histological type, the expression of miR-103a and miR-130a was significantly increased in the diffuse-type of GC compared to the intestinal-type. However, no influence of H. pylori infection was observed on the expression levels of mRNA and miRNAs analyzed. Moreover, the miRNA:mRNA interaction network showed several interrelations between the miRNAs and their target genes, highlighting miR-19a and miR-103a, which has as predicted or validated target a large number of genes in the TNF-α pathway, including TNF, TNFR1, TNFR2, CFLIP, TRADD, CASP3 and CASP8.

Our findings show that cell survival genes mediated by TNF/TNFR2 binding is up-regulated in GC favoring its pro-tumoral effect, while pro-apoptotic genes as CASP3 and TNFR1 are down-regulated, indicating disbalance between apoptosis and cell proliferation processes in this neoplasm. This process can also be influenced by an intricate regulatory network of miRNA:mRNA.

• Gastric cancer
• Tumor necrosis factor-α signaling
• TNFR1
• TNFR2
• Cellular survival
• MicroRNAs

• CREBRF
• TRIM2
• angiogenesis
• high-density lipoproteins
• hypoxia
• inflammation

• Carcinogenesis/genetics
• Cell Hypoxia/genetics
• Cell Line
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Gene Expression Regulation/drug effects
• Gene Knockdown Techniques
• Humans
• Inflammation/genetics
• Inflammation/pathology
• Lipoproteins, HDL/genetics
• Lipoproteins, HDL/pharmacology
• Neovascularization, Pathologic/genetics
• Neovascularization, Pathologic/pathology
• Nuclear Proteins/genetics
• Phosphatidylcholines/pharmacology
• Recombinant Proteins/genetics
• Recombinant Proteins/pharmacology
• Tumor Suppressor Proteins/genetics

• gastric cancer
• meta-analysis
• microRNA
• prognosis

Human gastric cancer (GC) is characterized by a high incidence and mortality rate, largely because it is normally not identified until a relatively advanced stage owing to a lack of early diagnostic biomarkers. Gastroscopy with biopsy is the routine method for screening, and gastrectomy is the major therapeutic strategy for GC. However, in more than 30% of GC surgical patients, cancer has progressed too far for effective medical resection. Thus, useful biomarkers for early screening or detection of GC are essential for improving patients’ survival rate. MicroRNAs (miRNAs) play an important role in tumorigenesis. They contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors. Because of their stability in tissues, serum/plasma and other body fluids, miRNAs have been suggested as novel tumor biomarkers with suitable clinical potential. Recently, aberrantly expressed miRNAs have been identified and tested for clinical application in the management of GC. Aberrant miRNA expression profiles determined with miRNA microarrays, quantitative reverse transcription-polymerase chain reaction and next-generation sequencing approaches could be used to establish sample specificity and to identify tumor type. Here, we provide an up-to-date summary of tissue-based GC-associated miRNAs, describing their involvement and that of their downstream targets in tumorigenic and biological processes. We examine correlations among significant clinical parameters and prognostic indicators, and discuss recurrence monitoring and therapeutic options in GC. We also review plasma/serum-based, GC-associated, circulating miRNAs and their clinical applications, focusing especially on early diagnosis. By providing insights into the mechanisms of miRNA-related tumor progression, this review will hopefully aid in the identification of novel potential therapeutic targets.

• biomarker
• diagnosis
• gastric cancer
• microRNAs
• prognosis

Gastric cancer (GC) still keeps up high mortality worldwide with poor prognosis. Efficient and non-invasive prognostic biomarkers are urgently needed. MicroRNAs are non-coding RNAs playing roles in post-transcriptional gene regulation, which contribute to various biological processes such as development, differentiation and carcinogenesis. MicroRNA expression profiles have been associated with the prognosis and outcome in GC. MicroRNA prognostic biomarkers have been identified from blood or tissues samples, but with different prognostic features. Understanding the various roles of microRNAs in different sample sources of GC will provide deep insights into GC progression. In this review, we highlight the distinct prognostic roles of microRNAs biomarkers in blood and tissue according to their relationships with prognostic parameters, survival rates and target pathways. This will be useful for non-invasive biomarker development and selection in prognosis of GC.

• blood
• gastric cancer
• microRNA
• prognostic biomarker
• tissues

Single nucleotide polymorphisms (SNPs) within precursor microRNAs (miRNAs) can affect miRNAs expression, and may be involved in the pathogenesis of pulmonary tuberculosis (TB). This study aimed to investigate potential associations between the four precursor miRNA SNPs (miR-146a C > G, miR-149 T > C, miR-196a2 T > C, and miR-499 T > C) and susceptibility to pulmonary TB in the Chinese Uygur, Kazak, and Southern Han populations.

A case-control study was performed on Chinese Uygur (n = 662), Kazak (n = 612), and Southern Han (n = 654) populations using the PCR-PFLR method. The allele and genotype frequencies for all populations were analyzed. Linkage disequilibrium was performed, and different models of inheritance were tested.

The allele and genotype frequencies of the miR-499 SNP were significantly different between the TB patients group and the healthy control group in the Uygur population, and were found to be codominant, dominant, recessive and additive models in association with pulmonary TB. The haplotype CTCC showed significant correlation with pulmonary TB. The allele and genotype frequencies of miR-146a and miR-196a2 SNPs were significantly different between the two groups in the Kazak population. The miR-146a SNP was found to be codominant, recessive and additive models, whereas, the miR-196a2 SNP was found to be codominant, dominant, and additive models in association with pulmonary TB. The haplotypes TCCC and CCCT showed significant correlation with pulmonary TB.

The results suggested that susceptibility to pulmonary TB may be closely related to individual differences caused by genetic factors among different ethnic groups in China.

The online version of this article (doi:10.1186/s12879-015-0771-9) contains supplementary material, which is available to authorized users.

Gastric cancer (GC) is the fourth most commonly diagnosed type of cancer worldwide and has the second highest mortality rate of all cancer types. Classical genetics alone does not fully explain how GC occurs; however, epigenetics provides a partial explanation with regard to the cause of cancer. DNA methylation, the best-known type of epigenetic marker, represses the expression of tumor-suppressor genes and is involved in the pathogenesis of various types of human cancer, including GC. Micro (mi)RNAs are critical in the initiation, progression, metastasis and invasion of GC through gene regulation. The dysregulation of miRNAs is widely recognized as a hallmark of cancer. Recently, studies concerning DNA methylation of miRNAs in GC have been frequently reported, and these studies deepen the knowledge of how epigenetic regulation of miRNAs results in GC pathogenesis and indicate novel therapeutic strategies for GC. The present review provides an overview of the reported DNA methylation of miRNAs in GC.

• Mycobacterium tuberculosis
• Tuberculosis immunology
• Tuberculosis infection
• microRNA

• Biomarkers/blood
• Gene Expression Profiling
• Gene Expression Regulation
• Humans
• MicroRNAs/genetics
• Tuberculosis/diagnosis
• Tuberculosis/genetics
• Tuberculosis/immunology

• T15 LM009451 NLM NIH HHS
• 2T15LM009451-06 NLM NIH HHS