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The comprehensive expression analysis of circular RNAs in gastric cancer and its association with field cancerization.

ABSTRACT: 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.

SUBMITTER: Vidal AF

PROVIDER: S-EPMC5673933 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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The comprehensive expression analysis of circular RNAs in gastric cancer and its association with field cancerization.

Vidal Amanda Ferreira AF Ribeiro-Dos-Santos André M AM Vinasco-Sandoval Tatiana T Magalhães Leandro L Pinto Pablo P Anaissi Ana K M AKM Demachki Samia S de Assumpção Paulo Pimentel PP Dos Santos Sidney Emanuel Batista SEB Ribeiro-Dos-Santos Ândrea Â

Scientific reports 20171106 1

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 RN ...[more]

PMID: 29109417

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Project description: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 and progression of GC. hsa-miR-10a, -miR-21, -miR-135b, -miR-148a, -miR-150, -miR-215, -miR-483 and -miR-664a were able to discriminate NC from other tissues with great accuracy (AUC>0.85). Conclusion: The studied miRNAs are closely related to field cancerization, regulate genes important for gastric carcinogenesis and can be potentially useful as biomarkers in GC.

Project description:BackgroundMicroRNAs (miRNAs) play an important role in gastric carcinogenesis and have been associated with gastric field cancerization; however, their role is not fully understood in this process. We performed the miRNome sequencing of non-cancerous, adjacent to tumor and gastric cancer samples to understand the involvement of these small RNAs in gastric field cancerization.MethodsWe analyzed samples of patients without cancer as control (non-cancerous gastric samples) and adjacent to cancer and gastric cancer paired samples, and considered miRNAs with |log2(fold change)| > 2 and Padj < 0.05 to be statistically significant. The identification of target genes, functional analysis and enrichment in KEGG pathways were realized in the TargetCompare, miRTargetLink, and DAVID tools. We also performed receiver operating characteristic (ROC) curves and miRNAs that had an AUC > 0.85 were considered to be potential biomarkers.ResultsWe found 14 miRNAs exclusively deregulated in gastric cancer, of which six have potential diagnostic value for advanced disease. Nine miRNAs with known tumor suppressor activities (TS-miRs) were deregulated exclusively in adjacent tissue. Of these, five have potential diagnostic value for the early stages of gastric cancer. Functional analysis of these TS-miRs revealed that they regulate important cellular signaling pathways (PI3K-Akt, HIF-1, Ras, Rap1, ErbB, and MAPK signaling pathways), that are involved in gastric carcinogenesis. Seven miRNAs were differentially expressed in both gastric cancer and adjacent regarding to non-cancerous tissues; among them, hsa-miR-200a-3p and hsa-miR-873-5p have potential diagnostic value for early and advanced stages of the disease. Only hsa-miR-196a-5p was differentially expressed between adjacent to cancer and gastric cancer tissues. In addition, the other miRNAs identified in this study were not differentially expressed between adjacent to cancer and gastric cancer, suggesting that these tissues are very similar and that share these molecular changes.ConclusionOur results show that gastric cancer and adjacent tissues have a similar miRNA expression profile, indicating that studied miRNAs are intimately associated with field cancerization in gastric cancer. The overexpression of TS-miRs in adjacent tissues may be a barrier against tumorigenesis within these pre-cancerous conditions prior to the eventual formation or relapse of a tumor. Additionally, these miRNAs have a great accuracy in discriminating non-cancerous from adjacent to tumor and cancer tissues and can be potentially useful as biomarkers for gastric cancer.

Dataset Information

The comprehensive expression analysis of circular RNAs in gastric cancer and its association with field cancerization.

Publications

The comprehensive expression analysis of circular RNAs in gastric cancer and its association with field cancerization.

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