miRNome reveals new insights into the molecular biology of field cancerization in gastric cancer

Background: MicroRNAs (miRNAs) play an important role in gastric carcinogenesisand have been associated with field cancerization in gastric cancer; however, the role ofthese molecules is not fully understood in this process. We performed miRNomesequencing of non-cancer, adjacent to tumor and gastric samples, to understand theinvolvement of miRNAs in gastric field cancerization.Methods: We analyzed samples of patients without cancer as control (non-cancer) andadjacent to cancer and gastric cancer paired samples, and consider |log 2 (fold change)|>2and P-value<0.05 as a parameter. We also evaluated the biomarkers potential of thestudied miRNAs by using receiver operating characteristic (ROC) and the area undercurve (AUC>0.85).Results: We found fifteen miRNAs exclusively deregulated in gastric cancer, of whichsix have potential diagnostic value for advanced disease. Eleven were deregulatedexclusively in adjacent tissue, with ten up-regulated tumor suppressors (TS-miRs). Ofthese, five have potential diagnostic value for the early stages of gastric cancer. Thefunctional analysis of these TS-miRs demonstrates that they regulate important cellular2signaling pathways (PI3K-Akt, HIF-1, Ras, Rap1, ErbB and MAPK signalingpathways), that are involved in gastric carcinogenesis. Five miRNAs were differentiallyexpressed in both gastric cancer and adjacent regarding to non-cancer tissues; amongthem, hsa-miR-200a-3p and hsa-miR-873-5p have potential diagnostic value for earlyand advanced stages of the disease. Only hsa-miR-196-5p was differentially expressedbetween adjacent to cancer and gastric cancer tissues. In addition, the other miRNAsidentified in this study were not differentially expressed between adjacent to cancer andgastric cancer, suggesting that these tissues are very similar and that share thesechanges.Conclusion: Our results show that gastric cancer and adjacent tissues have anexpression profile for miRNAs analyzed very similar, indicating that miRNAs studiedare intimately associated with field cancerization in gastric cancer. The overexpressionof TS-miRs in adjacent tissue is likely an antitumor mechanism. Additionally, thesemiRNAs have great accuracy in discriminating non-cancer from other tissues and can bepotentially useful as biomarkers for gastric cancer.