Abstract
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.
Highlights
Gastric cancer (GC) is an aggressive disease that is considered the third leading cause of cancer death worldwide (Ferlay et al, 2015)
When miRNAs are deregulated in the human stomach, they compromise important pathways that regulate the normal functions of this organ (Zhang et al, 2014), contributing to the onset and progression of gastric carcinogenesis (Wu et al, 2014)
Our results show new deregulated miRNAs, which are potentially useful as biomarkers for this cancer and suggest a new molecular mechanism involved in the biology of field cancerization
Summary
Gastric cancer (GC) is an aggressive disease that is considered the third leading cause of cancer death worldwide (Ferlay et al, 2015). MicroRNAs are small non-coding RNAs (∼18–30 nt) that regulate gene expression post-transcriptionally, disrupting the expression of target mRNAs (Bartel, 2004; Wu et al, 2014). These molecules play an important role in multiple pathways and the processes responsible for the maintenance of healthy tissue homeostasis (Schneider, 2012; Runtsch et al, 2014). When miRNAs are deregulated in the human stomach, they compromise important pathways that regulate the normal functions of this organ (Zhang et al, 2014), contributing to the onset and progression of gastric carcinogenesis (Wu et al, 2014). 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
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