Background: The biological role of microRNAs (miRNAs) in field cancerization is unknown. To investigate the involvement of miRNAs in gastric field cancerization, we evaluated the expression profile of ten miRNAs and their diagnostic value. Methods: We used three groups of FFPE gastric samples: non-cancer (NC), cancer adjacent (ADJ) and gastric cancer (GC). The expression profiles of hsa-miR-10a , -miR-21, -miR-29c, -miR-135b , -miR-148a , -miR-150 , -miR-204 , -miR-215 , -miR-483 and -miR-664a were investigated using qRT-PCR. The results obtained by qRT-PCR were validated in Small RNA-Seq data from the TCGA database. The search for target genes of the studied miRNAs was performed in the miRTarBase public database and miRTargetLink tool, using experimentally validated interactions. In addition, we also performed the functional analysis of these genes using enrichment in KEGG pathways. The potential as biomarker was evaluated using a receiver operating characteristic (ROC) curve and the derived area under the curve (AUC>0.85) analysis. Results: The miRNAs hsa-miR-10a , -miR-21 , -miR-135b , hsa-miR-148a , -miR-150 , -miR-215 , -miR-204 , -miR-483 and -miR-664a were up-regulated in ADJ and GC compared to NC ( P <0.03); and hsa-miR-21 and -miR-135b were up-regulated in GC compared to ADJ ( P <0.01). Hsa-miR-148a , -miR-150 , -miR-215 , -miR-483 and -miR-664a were not differentially expressed between GC and ADJ, suggesting that both share similar changes ( P >0.1). The TS-miR hsa-miR-29c was up-regulated in ADJ compared to NC and GC ( P <0.01); we did not observe a significant difference in the expression of this miRNA between NC and GC. This feature may be an antitumor mechanism used by cancer-adjacent tissue because this miRNA regulates the BCL-2 , CDC42 and DMNT3A oncogenes. The expression level of hsa-miR-204 was associated with Helicobacter pylori infection status ( P <0.05) . Functional analysis using the genes regulated by the studied miRNAs showed that they are involved in biological pathways and cellular processes that are critical for the establishment of H. pylori infection and for the onset, development an...
Our results provide evidence of epigenetic alterations in non-atrophic chronic gastritis and intestinal metaplasia and suggest that hsa-miR-29c and hsa-miR-135b are promising biomarkers of gastric carcinogenesis.
Circular RNAs comprise a new class of long noncoding RNAs characterized by their 5′ and 3′ ends covalently joined. Previous studies have demonstrated that some circular RNAs act as microRNA sponges, and are associated with cellular proliferation in cancer. We were the first to analyze the global expression of circular RNAs in samples of patients without gastric cancer, gastric cancer, and matched tumor-adjacent gastric tissue. Among the samples, we identified 736 previously annotated circular RNAs by RNA-Seq. The tumor-adjacent tissue presented the higher abundance of circular RNAs and could not be considered as a normal tissue, reinforcing the notion of field effect in gastric cancer. We identified five differentially expressed circular RNAs that may be potential biomarkers of this type of cancer. We also predicted candidate microRNAs targets of the highest expressed circular RNAs in gastric tissues and found five miRNAs. Overall, our results support the hypothesis of circular RNAs representing a novel factor in the dynamic epigenetic network of gene regulation, which involves the microRNAs, its mRNAs targets, and the circular RNAs-derived genes. Further studies are needed to elucidate the roles and the functional relevance of the circular RNAs in human diseases.
Mitochondria are organelles that perform major roles in cellular operation. Thus, alterations in mitochondrial genome (mtGenome) may lead to mitochondrial dysfunction and cellular deregulation, influencing carcinogenesis. Gastric cancer (GC) is one of the most incident and mortal types of cancer in Brazil, particularly in the Amazon region. Here, we sequenced and compared the whole mtGenome extracted from FFPE tissue samples of GC patients (tumor and internal control – IC) and cancer-free individuals (external control – EC) from this region. We found 3-fold more variants and up to 9-fold more heteroplasmic regions in tumor when compared to paired IC samples. Moreover, tumor presented more heteroplasmic variants when compared to EC, while IC and EC showed no significant difference when compared to each other. Tumor also presented substantially more variants in the following regions: MT-RNR1, MT-ND5, MT-ND4, MT-ND2, MT-DLOOP1 and MT-CO1. In addition, our haplogroup results indicate an association of Native American ancestry (particularly haplogroup C) to gastric cancer development. To the best of our knowledge, this is the first study to sequence the whole mtGenome from FFPE samples and to apply mtGenome analysis in association to GC in Brazil.
Identifying a microbiome pattern in gastric cancer (GC) is hugely debatable due to the variation resulting from the diversity of the studied populations, clinical scenarios, and metagenomic approach. <i>H. pylori</i> remains the main microorganism impacting gastric carcinogenesis and seems necessary for the initial steps of the process. Nevertheless, an additional non-<i>H. pylori</i> microbiome pattern is also described, mainly at the final steps of the carcinogenesis. Unfortunately, most of the presented results are not reproducible, and there are no consensual candidates to share the <i>H. pylori</i> protagonists. Limitations to reach a consistent interpretation of metagenomic data include contamination along every step of the process, which might cause relevant misinterpretations. In addition, the functional consequences of an altered microbiome might be addressed. Aiming to minimize methodological bias and limitations due to small sample size and the lack of standardization of bioinformatics assessment and interpretation, we carried out a comprehensive analysis of the publicly available metagenomic data from various conditions relevant to gastric carcinogenesis. Mainly, instead of just analyzing the results of each available publication, a new approach was launched, allowing the comprehensive analysis of the total sample amount, aiming to produce a reliable interpretation due to using a significant number of samples, from different origins, in a standard protocol. Among the main results, <i>Helicobacter</i> and <i>Prevotella</i> figured in the “top 6” genera of every group. <i>Helicobacter</i> was the first one in chronic gastritis (CG), gastric cancer (GC), and adjacent (ADJ) groups, while <i>Prevotella</i> was the leader among healthy control (HC) samples. Groups of bacteria are differently abundant in each clinical situation, and bacterial metabolic pathways also diverge along the carcinogenesis cascade. This information may support future microbiome interventions aiming to face the carcinogenesis process and/or reduce GC risk.
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