173PD MicroRNA MIR21, T cells, and PTGS2 expression in

Abstract

Background Prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase-2) produces inflammatory mediator prostaglandin E2 (PGE2), and contributes to suppresses antitumorT-cell-mediated immunity. PTGS2-driven inflammatory responses can induce tumorexpressionof microRNAMIR21 (miR-21) thatcanincreaselocalPGE2levelby downregulatingPGE2-metabolizingenzymes. Thus,wehypothesizedthattheprognostic associationoftumorMIR21 expressionlevelincolorectalcarcinomamightdependon PTGS2 expression and that tumor MIR21 expression might be inversely associated with T- cell density in colorectal carcinoma tissue. Methods Utilizing 765 rectal and colon cancer specimens in the Nurses' Health Study and the Health Professionals Follow-up Study, we measured MIR21 expression by quantitative reverse-transcription PCR, and PTGS2 expression by immunohistochemistry. Densities of CD3+, CD8+, CD45RO (pTpRC)+ and FOXP3+ cells in tumor tissue were determined by tissue microarray immunohistochemistry and computer-assisted image analysis. Multivariable analyses were conducted to assess the statistical interaction between MIR21 and PTGS2 in colorectal cancer-specific survival analysisandtheassociationofMIR21 expression withT-celldensity, controlling for potential confounders including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation level, and KRAS, BRAF, and PIK3CA mutations. Results The association between MIR21 expression and colorectal cancer-specific mortality was statistically significant in PTGS2-high cancers (multivariable hazard ratio ofthehighestvs. lowestquartileofMIR21, 2.28;95%confidenceinterval, 1.42 to3.67; Ptrend= 0.0004) butnotinPTGS2-absent/lowcancers (Ptrend= 0.22;Pinteraction= 0.0004). Tumor MIR21 expression was inversely associated with densities of CD3+ and CD45RO+ cells (Pt rend < 0.0005). Conclusions:Ourdatasupportapossibleroleoftumorepigeneticderegulationbynon- coding RNA in suppressing antitumor T-cell-mediated immune response, and suggest MIR21 as a potential target for immunotherapy and treatment in colorectal cancer. Legal entity responsible for the study USA National Institutes of Health (NIH) Funding USA National Institutes ofHealth (NIH) Disclosure All authors have declared no conflicts ofinterest.