AUTHOR=Pereira Adenilson , Moreira Fabiano , Vinasco-Sandoval Tatiana , Cunha Adenard , Vidal Amanda , Ribeiro-dos-Santos André M. , Pinto Pablo , Magalhães Leandro , Assumpção Mônica , Demachki Samia , Santos Sidney , Assumpção Paulo , Ribeiro-dos-Santos Ândrea 

TITLE=miRNome Reveals New Insights Into the Molecular Biology of Field Cancerization in Gastric Cancer

JOURNAL=Frontiers in Genetics

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2019.00592

DOI=10.3389/fgene.2019.00592

ISSN=1664-8021

ABSTRACT=<sec><title>Background</title><p>MicroRNAs (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.</p></sec><sec><title>Methods</title><p>We 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 |log<sub>2</sub>(<italic>fold change</italic>)| &gt; 2 and <italic>Padj</italic> &lt; 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 &gt; 0.85 were considered to be potential biomarkers.</p></sec><sec><title>Results</title><p>We 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, <italic>hsa-miR-200a-3p</italic> and <italic>hsa-miR-873-5p</italic> have potential diagnostic value for early and advanced stages of the disease. Only <italic>hsa-miR-196a-5p</italic> 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.</p></sec><sec><title>Conclusion</title><p>Our 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.</p></sec>